Embryology, Malformations, and Rare Diseases of the Cochlea

. 2021 Apr 30;100(Suppl 1):S1–S43. doi: 10.1055/a-1349-3824

Table 1 Rare diseases of the cochlea.

Name	Cause	Gene	Inheritance	Incidence	Therapy	Symptoms	Annotations
Autoimmune-mediated inner ear diseases
Cogan syndrome	Autoantibody-mediated (?) vasculitis with systemic manifestation ¹²⁷	-	-	About 300 cases worldwide ¹²⁷	Corticosteroids, cyclophosphamide, methotrexate, mycophenolate mofetil, azathioprine, infliximab ¹²⁷	Non-syphilitic interstitial keratitis (IK) with audiovestibular Menière-like symptoms ¹²⁷ ; typical and atypical types are described: in atypical types, the eye involvement manifests with non-IK inflammatory ocular symptoms	Max. 2 years between the affection of both organs (eye and inner ear) ¹²⁷ ; is considered as vasculitis ¹¹⁷
Muckle-Wells syndrome	Excessive release of IL1beta ¹²⁸	NLRP3 ¹²⁸	aut. dom. ¹²⁸	1–3:1,000,000	Anakinra ¹²⁸	Fever, skin rash, musculo-skeletal symptoms and conjunctivitis. Progressive sensorineural hearing loss and kidney failure ¹²⁸	Belongs to the group of CAPS (cryopyrin-associated periodic syndrome); Muckle-Wells syndrome, FCAS (familial cold auto-inflammatory syndrome) and NOMID (neonatal onset multisystem inflammatory disorder) have a common causative gene defect (NLRP3)
Neonatal onset multisystem inflammatory disease (NOMID)	Excessive release of IL1beta ¹²⁹	CIAS1/NLRP3 ¹²⁹	aut. dom. ¹²⁹	Very rare, 100 cases have been described worldwide ¹²⁹	Anakinra ¹²⁹	Skin rash, chronic meningitis, fever, joint inflammation ¹²⁹
Relapsing polychondritis	Autoimmune-mediated inflammation of cartilage ¹³⁰		Multifactorial etiology ¹³⁰	1:285,000 ¹³⁰	Glucocorticoids ¹³⁰	Cartilage inflammation, uveitis, vasculitis, hearing loss in 50%, vertigo ¹³⁰
Vogt-Koyanagi-Harada disease	T cell mediated destruction of melanin-containing tissue ¹³¹	-	-	1:400,000 ¹³¹	Glucocorticoids ¹³¹	Uveitis, alopecia, meningism ¹³¹
Vascular
Behçet’s syndrome	Vasculitis, HLA-B51-associated (?)	-	-	Regional differences, 1:100,000 in Germany	Symptom-based, steroids, non-steroidal antiphlogistics ¹³²	Recurrent oral aphthae, genital ulcers, eye and skin lesions ¹³²	Kidneys and peripheral nerve system are very rarely affected
Eosinophilic granulomatosis with polyangiits (‘EGPA; formerly: Churg-Strauss syndrome)	Allergic granulomatosis with polyangiitis, antinuclear cytoplasmic antibody-associated vasculitis ¹³³ ¹³⁴	-	-	2.4:1,000,000	High-dose glucocorticoids, cyclophosphamide, zafirlukast (leukotriene antagonist) ¹³⁴ ¹³⁵ , mepolizumab (anti-interleukin-5 antibody) ¹³⁶	Blood eosinophilia, heart failure, allergic rhinitis, asthma, vasculitis with involvement of the skin, heart, lung, gastrointestinal tract, neural system ¹³³ ¹³⁴ ¹³⁶	Triphasic disease, manifestation in the inner ear in the 3 ^rd phase is rarely observed ¹³³ , EGPA is classified as ANCA-associated vasculitis among minor vessel vasculitis
Generalized arterial calcification in infants	Calcium deposits in the arteries ¹³⁷	ENPP1, ABCC6 ¹³⁷	Aut. rec. ¹³⁷	1:391,000 ¹³⁷	Bisphosphonates ¹³⁷	Heart failure, stroke, pseudoxanthoma elasticum ¹³⁷	Also conductive hearing loss ¹³⁷
Hereditary hemorrhagic telangiectasia (Weber-Osler-Rendu disease)	Vascular dysplasia, arterio-venous fistulas/malformations ¹³⁸	Chromosomes 9q and 12q ¹³⁸	Aut. dom ¹³⁸	1–2:100,000 ¹³⁸		Vascular malformation of multiple organs (kidney, gastrointestinal tract, liver, lung, brain), recurrent epistaxis as most frequent symptom
Kawasaki disease	Necrotizing vasculitis ¹³⁹ ¹⁴⁰	Unknown, corona virus (?)		>300,000 cases have been described worldwide ¹³⁹	Intravenous application of immunoglobulins, aspirin	Fever, skin rash, conjunctivitis, cardiac complications	Appears nearly exclusively in children
Norrie disease	Disorder of the angiogenesis of eye and inner ear ¹⁴¹	NDP ¹⁴¹	X-linked	More than 400 cases have been described worldwide		Retinal detachment and progressive hearing loss ¹⁴¹
Susac’s syndrome	CD8 T cell-mediated autoimmune-microangiopathic endotheliopathy ¹⁴²	-	-	Slightly more than 300 cases have been described worldwide ¹⁴²	Anti-platelet medicine, anti-coagulants, immunosuppressive treatment with e.g., cyclophosphamide, intravenous immunoglobulins, mycophenolate mofetil, azathioprine, methotrexate, natalizumab ¹⁴²	Visual field loss, visual loss, neurological symptoms, cephalgia ¹⁴²
Granulomatosis with polyangiitis (GPA; formerly: Wegener’s granulomatosis)	Autoimmune vasculitis ¹⁴³	-	-	1:6,400 ¹⁴³	Glucocorticoids, rituximab ¹⁴³	Sinusitis, tracheal stenosis, kidney failure, pneumonia, mastoiditis ¹⁴³	ANCA+ ¹⁴³
Malformations
Labyrinthine aplasia	Complete aplasia, when the development is disturbed before or at the beginning of the 3 ^rd week of gestation; may also be thalidomide-induced ¹⁴⁴ ¹⁴⁵		Increased risk in cases of consanguine parents ¹⁴⁶	2% of all inner ear malformations	ABI	Facial nerve paresis or weakness ¹⁴⁶	Synonym: Michel deformity, Michel aplasia, bony canal of the internal carotid artery may be missing ¹⁴⁶
Otocyst deformity	Developmental arrest in the 3 ^rd week of gestation ¹⁴⁶		Increased risk in cases of consanguine parents	1% of all inner ear malformations	ABI	Congenital deafness, possible facial nerve palsy or weakness ¹⁴⁶	Synonym: common cavity (according to Jackler)
Cochlear aplasia				5% of all inner ear malformations ¹⁰⁰	CI, ABI ¹⁰⁰	Congenital deafness	Speech understanding with CI is possible ¹⁰⁰
Cochlear hypoplasia (isolated)	Frequently occurs in BOR syndrome ¹⁰⁸			13% of all inner ear malformations ¹⁰⁸	CI	Deafness, high-grade hearing loss	Broad spectrum, nearly normal form up to a small basal cyst ¹⁰⁸
Complete aplasia of the semicircular canals	(includes hypoplastic cochlea and small vestibule with saccule) ¹⁴⁷	Often associated with CHARGE; single case reports with e.g., Wildervanck, Noonan, Goldenhar, or VACTERL* ¹⁴⁸		16% of all inner ear malformations	CI	Deafness, high-grade hearing loss ¹⁴⁷	Main criterion of CHARGE
Incomplete partition type 2 (IPT2)				21% of all inner ear malformations ¹⁴⁹	CI	Deafness, high-grade hearing loss	Mondini malformation in the actual sense ¹⁴⁹
Incomplete partition type 1 (IPT1)		FOXF2 ¹⁵⁰		9% of all inner ear malformations ¹⁴⁹	CI	Deafness, high-grade hearing loss	Synonym: common cavity (E. Cock); cystic cochleovestibular malformation, figure-8 deformity
X-linked deafness (inner ear malformation called IPT3)	Different mutations of POU3F4 ⁸⁹	POU3F4		3% of all inner ear malformations	Hearing aids, CI ¹⁵¹	Variable hearing loss	Synonym: gusher, IPT3 – even if it is not in line with other incomplete partitions; often associated with hamartoma of the tuber cinereum ⁹²
Modiolus aplasia				1% of all inner ear malformations ¹¹⁰
Hypoplasia or aplasia of the vestibulocochlear nerve or isolated of the cochlear nerve							Mostly combined with severe inner ear malformations ¹¹⁰
* VACTERL describes an association of congenital malformations that has at least three of these symptoms: esophageal atresia, kidney malformation, heart defect, vertebral defects, anorectal malformations, and radial extremity malformations
Chromosomal
3p deletion syndrome	Deletion of the short arm of chromosome 3 ¹⁵² ¹⁵³	Chromosome 3 ¹⁵² ¹⁵³	De novo ¹⁵² ¹⁵³	Very rare		Microcephaly, triangular shape of the face, flat occiput, hypertelorism, polydactyly, cryptorchidism, renal and cardiac defects ¹⁵² ¹⁵³
10p deletion syndrome	Deletion of the short arm of chromosome 10 ¹⁵⁴	Chromosome 10 ¹⁵⁴		Very rare, about 50 cases are known ¹³⁵		Craniofacial malformations, growth disorders, congenital heart defects, hypoparathyroidism, immunodeficiency, mental retardation ¹⁵⁴	Haploinsufficiency 10p15 causes also HDR1 syndrome ¹⁵⁵
Cri-du-chat syndrome, 5p deletion syndrome	Deletion of the short arm of chromosome 5 ¹⁵⁶	Haploinsufficiency of various genes, e.g., TERT, MARCH6, CTNND2, and SLC6A3 on chromosome 5 ¹⁵⁶	De novo ¹⁵⁶	1:15,000–1:50,000 ¹⁵⁶		High-frequency cry (cri-du-chat), microcephaly, facial dysmorphia, delayed speech acquisition, mental disability ¹⁵⁶	Most frequent chromosomal defect ¹⁵⁶ , neural hearing loss ¹⁵⁷
DiGeorge anomaly ¹⁵⁴ , chromosome 22q11.2 deletion	Haploinsufficiency of DiGeorge syndrome critical region gene 2 (DGCR2) ¹⁵⁵	DGCR2, centromere deletion of chromosome 10, 22q11.2 deletion ¹⁵⁴ ¹⁵⁸		1:4,000 ¹⁵⁸	Allogenic thymus tissue transplantation ¹⁵⁹	Thymus aplasia, congenital developmental disorder, T cell deficiency, hypocalcaemia, cardiovascular malformation, facial dysmorphia ¹⁵⁴
Cat eye syndrome, Schmid-Fraccaro syndrome	Anomaly of chromosome 22, 22 ¹⁶⁰ ¹⁶¹	Chromosome 22 ¹⁶⁰ ¹⁶¹	Aut. dom. (160, 161]	1:100,000 ¹⁶⁰ ¹⁶¹	Symptom-based, experimental: GNE-886, selective inhibitor of the cat eye syndrome chromosome region candidate 2 bromodomain ¹⁶²	Coloboma, anal atresia, heard defects, preauricular tags ¹⁶⁰ ¹⁶¹
Mosaic trisomy 9	Partial trisomy ¹⁶³ ¹⁶⁴ ¹⁶⁵	Chromosome 9 ¹⁶³ ¹⁶⁴ ¹⁶⁵				Growth retardation, muscular weakness, mental disability, microcephaly, micrognathia, characteristic palpebral fissures, skeletal anomalies, microphthalmia, cleft palate, hydrocephalus ¹⁶³ ¹⁶⁴ ¹⁶⁵	Partly very mild courses that remain undiagnosed ¹⁶³
Mosaic trisomy 22	Partial trisomy ¹⁶⁶ ¹⁶⁷	Chromosome 22 ¹⁶⁶ ¹⁶⁷				Mental disability, growth disorders, failure to thrive, craniofacial asymmetry, microcephaly, brachycephaly, hypoplasia of the midface, preauricular tags, flat nose, micrognathia, cleft palate ¹⁶⁶ ¹⁶⁷	Overlapping with cat eye syndrome?
Pallister-Killian mosaic syndrome	Chromosome duplication (12p) ¹⁶⁸			150 cases worldwide ¹⁶⁸		Muscular hypotonia and telecanthus ¹⁶⁸
Smith-Magenis syndrome ¹⁶⁹	17p11.2 deletion ¹⁶⁹	RAI1 ¹⁶⁹		1:15,000 ¹⁶⁹		Brachycephaly, broad square-shaped face, hypotonia, sleep disorder, self-injury ¹⁶⁹	Initially conductive hearing loss, the progressive sensorineural hearing loss at the age of 10 years
Trichorhinophalangeal syndrome type II	Chromothripsis, chromosome deletion (q8) ¹⁷⁰	TRPS1, EXT1 ¹⁷⁰		<60 worldwide ¹⁷⁰		Thin hair, short stature ¹⁷⁰	Langer-Giedion syndrome ¹⁷⁰
Metabolic diseases
Acyl-Co-A dehydrogenase deficiency (Schindler syndrome)	Lactate acidosis, mitochondrial disease of the complex I concerning the respiratory chain ¹⁷¹	ACAD9 ¹⁷¹ ¹⁷²	Aut. rec. ¹⁷¹	Very rare, 24 patient from 12 families have been described up to 2016 ¹⁷²	Riboflavin substitution is effective in some patients ¹⁷¹ ¹⁷²	Neurological, muscular, hepatic, and cardiac manifestation ¹⁷¹ ¹⁷²
Alpha galactosidase deficiency (Fabry’s disease)	Lysosomal storage disease, glycol-sphingolipid catabolism ¹⁷³		X-chromosomal	1:40,000–1:117,000	Agalsidase beta (enzyme substitution) ¹⁷⁴	Progressive kidney disease, cardiomyopathy, cerebrovascular complications, neuropathic pains, apoplexy ¹⁷³	Atrophy of the organ of Corti, stria vascularis, and the spiral ligament in 2 post-mortem analyses ¹⁷³
Alpha mannosidosis	Deficiency of the lysosomal alpha D mannosidase	MAN2B1	Aut. rec.	1:500,000 ¹³⁵	Velmanase alpha (Lamzede®) by Chiesi ¹⁷⁵ ¹⁷⁶	Recurrent infections, muscular weakness, skeletal and facial deformities, ataxia, hepatosplenomegaly, hydrocephalus, macroglossia, prognatism, strabism, hyperopia or myopia; immune deficiency, hypersomnia, psychiatric diseases, mental disability ¹³⁵ ¹⁷⁷	Lysosomal storage disease; different subtypes, severity and age at disease onset ¹³⁵ ¹⁷⁷
Biotinidase deficiency	Disorder of all mitochondrial caboxylases ¹⁷⁸	BTD ¹⁷⁸	Aut. rec. ¹⁷⁸	1:50,000 ¹⁷⁸	Biotin substitution	Seizures, muscular weakness, ataxia, developmental delay, visual loss, alopecia, skin rash ¹⁷⁸	Neuromyelitis optica spectrum disorders (NMOSDs) Holocarboxylase synthetase (HCLS) deficiency; incidence of 1:200,000
Brown-Vialetto-van-Laere syndrome (riboflavin transporter deficiency)	Deficiency of riboflavin transporter proteins	SLC52A2, SLC52A3{179]	Aut. rec. ¹⁷⁹	Less than 100 cases are known ¹⁷⁹	Riboflavin substitution ¹⁸⁰	Progressive pontobulbar paralysis, respiratory insufficiency, muscular weakness, facial nerve palsy, ptosis, dysphagia, and ataxia ¹⁷⁹
Camurti-Engelmann syndrome, diaphyseal hyperostosis or sclerosis	Permanent activity of the transforming growth factor beta 1 causing increased bone density and reduced fat and muscle tissue ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁴	TGFB1 ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁴	Aut. dom. ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁴	>300 cases are described worldwide ¹⁸⁵	Experimental approaches with TGF beta receptor antagonists ¹⁸⁵	Hyperostosis of the long bones, diffuse thickening of the skull base, ophthalmopathy, cephalgia, vasculopathy, pains, muscular weakness ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁴	Craniotubular bone disease, progressive stenosis of the internal auditory canal ¹⁸³ ¹⁸⁶
Chanarin-Dorman syndrome	Abhydrolase deficiency and lacking activation of fat triglyceride lipase ¹⁸⁷	ABHD5 ¹⁸⁷	Aut. rec.	More than 128 known cases	Symptom-based, fat-free diet	Congenital ichthyosiform erythroderma, hypothyroidism, neurological symptoms, liver function disorder, cataract, ectropion ¹⁸⁷	Neutral lipid storage disease with ichthyosis
Craniometaphyseal dysplasia	Inhibition of the regulated bone remodeling by extracellular pyrophosphate accumulation ¹⁸⁸	ANKH, GJA1	Aut. rec. or aut. dom.	Very rare	Symptom-based	Hypertelorism, dolichocephaly, proptosis, prominent mandible, thickening of the skull bone, retarded dentition ¹⁸⁸ ¹⁸⁹ ¹⁹⁰
Familial hypophosphatemia	Phosphate loss due to increased secretion of the phosphaturic hormone fibroblast growth factor 23 ¹⁹¹		X-chrom., more rarely aut. rec., aut. dom. ¹⁹¹ ¹⁹²	3:100,000 for X-linked	Symptom-based, phosphate and vitamin D	Rickets, abnormal gait, deformity of the lower extremities, retarded growth, dental abscesses ¹⁹¹
Farber lipogranulomatosis	Lysosomal storage disease, acid ceramidase deficiency ¹⁹³ ¹⁹⁴	ASAH1 ¹⁹³ ¹⁹⁴	Aut. rec. ¹⁹³ ¹⁹⁴	201 cases were known in 2018	Symptom-based	Subcutaneous nodes, deformed joints, progressive hoarseness, special types of muscle atrophy and progressive myoclonal epilepsy ¹⁹³ ¹⁹⁴
Fibrodysplasia ossificans progressive	Heterotopic ossifications ¹⁹⁵ ¹⁹⁶	ACVR1/ALK2 ¹⁹⁵ ¹⁹⁶	Aut. dom. ¹⁹⁵ ¹⁹⁶	1:2,000,000 ¹⁹⁵ ¹⁹⁶	Symptom-based ¹⁹⁵ ¹⁹⁶	Missing nails, progressive heterotopic ossification, hypoplasia of the brainstem, cognitive and motor developmental disorders
Fibrous dysplasia (Jaffe-Lichtenstein syndrome)	Disorder of the osteogenesis due to overproduction of cAMP, phosphorylation CREB and activation of cAMP-depending protein kinase (PKA) ¹³⁵	GNAS	Non-hereditary	Unknown	Bisphosphonates	Exchange of normal bone and bone marrow with fibrous connective tissue and immature trabecular bone ¹³⁵	Often conductive but sometimes also sensorineural hearing loss ¹³⁵
Kernicterus	Deposit of unconjugated bilirubin ¹³⁵		Sporadic	Often occurs in premature births		Hyperbilirubinemia ¹³⁵	Neural and central hearing loss ¹³⁵
Congenital disease of the glycosylation	Defect biosynthesis of glycanes	Several genes ¹⁹⁷	Aut. rec., rarely x-linked	Less than 100 cases per type ¹⁹⁸	Symptom-based, mannose or D galactose supplementation ¹⁹⁸	Multisystem manifestation, neurological symptoms, mental disability, cardiomyopathy, edema, facial deformities ¹⁹⁸	More than 130 types are described ¹⁹⁸ , defect N, O, and combined N and O glycosylation as well as lipid glycosylation ¹⁹⁹
Leigh syndrome (infantile necrotizing encephalopathy)	Congenital lactate acidosis, pyruvate dehydrogenase deficiency	PDHA, pyruvate dehydrogenase (E1) a subunit ²⁰⁰ ²⁰¹	X-linked ²⁰⁰ ²⁰¹	1:40,000–70,000	High-dose thiamine substitution ²⁰⁰ ²⁰¹	Peripheral neuropathies, chorea, Parkinson-like symptoms, cognitive deficits, necrotic lesions in the brain, hypertrophic cardiomyopathy ²⁰⁰ ²⁰¹
Mucopolysaccharidosis type 1 (formerly: Hurler or Scheie syndrome)	Lysosomal storage disease ²⁰²	NEU1 ²⁰²	Aut. rec. ²⁰²	1:42,000,000 ²⁰²		Ataxia, myoclonus, progressive visual loss ²⁰²
Mucopolysaccharidosis type II (Hunter)		IDS ²⁰³	X-linked, recessive ²⁰³	0.5–1:100,000 ²⁰³	Symptom-based, enzyme substitution therapy	Coarse facial features, skeletal deformities and stiff joints, growth retardation with hyposomia, impairment of respiration and heart including diffuse valvulopathy, inguinal and umbilical hernia, hepatosplenomegaly, neurological involvement in at least two third of the cases, adeno-tonsillar hypertrophy, obstructive sleep apnea, retinal degeneration ²⁰³	Lysosomal storage disease
Niemann-Pick-C syndrome ²⁰⁴	Lysosomal storage disease; disturbed cholesterol and fatty acid transport ²⁰⁴	NPC 1; NPC 2 ²⁰⁴	Aut. rec.	1:100,000–250,000 ²⁰⁴		Progressive neurodegeneration, hepatomegaly ²⁰⁴	Mild to high-grade hearing loss, also neuropathy
NGLY1 deficiency	Inability to remove N-glycan ²⁰⁵	NGLY1 ²⁰⁵	Aut. rec.	<63 patients worldwide	-	Neuropathy, corneal ulcerations, dystonia
Oculo-auriculo-vertebral dysplasia (Goldenhar syndrome) ²⁰⁶	Unknown		-	1:30,000–1:40,000 ²⁰⁶		Unilateral malformation of cheekbones, jaw, mouth, ears, eyes, and/or vertebrae ²⁰⁶	Part of Goldenhar syndrome, aural atresia, internal auditory canal may be malformed ²⁰⁶
Primary distal renal tubular acidosis (distal RTA, type)	Proton pump subunit B1 is also expressed in the stria vascularis ²⁰⁷ ; some patients also have an enlarged vestibular aqueduct	ATP6V1B1;ATP6V0A4 ²⁰⁷	Aut. rec.	-	Correction of metabolic deficits ²⁰⁷	Metabolic acidosis and osteomalacia ²⁰⁷	Hearing loss is variable and is often not regressive under alkali therapy
Pompe disease (glycogenosis type 2)	Glycogen deposits in muscles ²⁰⁸	GAA ²⁰⁸	Aut. rec. ²⁰⁸	1:40,000 ²⁰⁸		Congenital or progressive muscular weakness, respiratory insufficiency ²⁰⁸	Mild hearing loss, possible stapedius muscle weakness ²⁰⁸
Refsum disease	Failure of metabolism of phytanic acid ²⁰⁹ ²¹⁰ ²¹¹	PHXH; PEX7 ²⁰⁹ ²¹⁰ ²¹¹	Aut. rec.	1:1,000,000 ²⁰⁹ ²¹⁰ ²¹¹		Retinitis pigmentosa, ichthyosis, anosmia ²⁰⁹ ²¹⁰ ²¹¹	Onset of the symptoms at an age of 10–20 years; mild to high-grade hearing loss, also neuropathy ²⁰⁹ ²¹⁰ ²¹¹ , Bamiou et al.
Rogers syndrome; thiamin responsive megaloblastic anemia	Thiamin pyrophosphokinase deficiency ²¹² ²¹³ ; highly-affine thiamin transporter	SLC19A2 ²¹² ²¹³	Aut. rec. ²¹² ²¹³	Less than 80 cases are known ¹⁷⁵	Thiamin substitution ²¹² ²¹³	Diabetes mellitus, megaloblastic anemia ²¹² ²¹³	Thiamin pyrophosphokinase=highly affine thiamin transporter
Schindler syndrome	Lysosomal storage disease ²¹⁴	NAGA ²¹⁴	Aut. rec. ²¹⁴	<1:200,000 ²¹⁴		Progressive neurodegeneration with hypotonia and telangiectasias in the adult type ²¹⁴
Keratoses and ichthyoses
Autosomal recessive congenital ichthyosis	Non-syndromic keratin disorder due to mutation of genes that regulate the keratinocyte differentiation	Different, e.g., TGM1, ALOXE3, ALOX12B, PNPLA1, and CERS2 ²¹⁵	Aut. rec.	1:100,000	Symptom-based	Heat intolerance, pruritus, growth disorders, visual disorders ²¹⁵	Different types, syndromic types are e.g., KID
De Sanctis-Cacchione syndrome	Xeroderma pigmentosum, severe DNA reparation disorder (defective nucleotide excision reparation)	XPA or ERCC2/XSD ²¹⁶	Aut. rec. ²¹⁶ ²¹⁷	About 200 cases are known	Symptom-based	Cutaneous photosensitivity, microcephaly, mental disability, hyposomia, hypogonadism, spasm, peripheral neuropathy ²¹⁶ ²¹⁷
Harlequin ichthyosis	Hyperkeratosis with defective keratinocyte transmembranous lipid transporter protein and disorder of the lipid transport to the stratum corneum ²¹⁸	ABCA12 ²¹⁸	Aut. rec.	1:500,000 ²¹⁸	Symptom-based	Thickened yellowish skin with fissures, ectropium, eclabium, round open mouth, missing scalp hair as well as cilia and eyebrows ²¹⁸	Severest type of congenital ichthyosis
Keratosis-ichthyosis deafness syndrome (KID)	Connexin-26 disorder ²¹⁹	GJB2 ²¹⁹	Sporadic, also aut. dom. and rec. cases are known ²¹⁹	Less than 100 cases are known ²¹⁹		Erthrokeratodermic follicular hyperkeratosis, psoriasisiform or verrucous plaques, palmoplantar keratodermatosis, conjunctivitis, hypotrichosis ²¹⁹	Characteristic triad: ichthyosiform erthrodermatosis, high-grade sensorineural hearing loss, vascularizing keratitis ²¹⁹
Hereditary palmoplantar keratosis (PKK)	Connexin-26-related change of the Cx43 gap junctions (increased semicanal activity) ²²⁰	GJB2 (Cx26-H73R, und Cx26-S183F) ²²⁰	Aut. dom. or mitoch. ¹⁷⁵	Very rare,<1:1,000,000 ¹⁷⁵		Palmar and plantar hyperkeratosis ²²⁰
Trichothiodystrophy	Nucleotide excision reparation	ERCC2, ERCC3, TTDA, TTDN1, GTF2E2	Aut. rec.	1:1,000,000		Dermal ichthyosis, mental and growth retardation, hypogonadism ²²¹	Variable manifestations, BIDS (brittle hair, impaired intelligence, decreased fertility, and short stature), IBIDS (with ichthyosis), PIBIDS (with photosensitivity), or Tay syndrome ²²¹
Syndromes
Alström syndrome	Ciliopathy ²²²	ALMS1 ²²²	Aut rec. ²²²	1–9:100,000 ²²²	CI	Photoreceptor dystrophy, obesity, type-2 diabetes, hyperlipidemia, acanthosis nigricans, hypogonadism, renal, pulmonary, and hepatic dysfunction, dilatative cardiomyopathy ²²²
Arts syndrome	Deficiency of phosphoribosyl pyrophosphate synthetase 1 ²²³	PRPS1 ²²³	X-linked	Very rare		Ataxia, mental retardation, hypotension, opticus atrophy, peripheral neuropathy ²²³
Barakat syndrome	Developmental disorder of the parathyroid, kidney, and inner ear ¹³⁵	GATA3 ²²⁴	Aut. dom.	180 patients worldwide ²²⁴	Symptom-based	Hypoparathyroidism, deafness, and kidney diseases; variably phenotypes are possible ²²⁴ ²²⁵
Bardet-Biedl syndrome	Cilipathy ¹³⁵ ²²⁶	21 different genes ²²⁶	Aut. rec.	About 1:150,000 ²²⁷	Symptom-based; experimental gene therapeutic approaches ²²⁸	Obesity, pigmental retinopathy, kidney disease, anosmia, hypogonadism, situs inversus ²²⁶ ²²⁷ ²²⁸	Incidence is higher in regions with frequent consanguinity ²²⁷
Bartter and Gitelman syndrome	Channelopathy ²²⁹	Several, e.g., KCNJ1, NKCC, NCCT, BSND, ROMK, IBS, CLCNKB, SLC12A1 SLC12A3 ²²⁹ ²³⁰	Aut. rec. ²²⁹			Hypokaliemia, hypochloremic metabolic alkalosis, polyuria, polydipsia	Bartter type 1–4, Gitelman (SLC12A3) as mild, late onset type
Björnstad syndrome	Chaperonopathy, disorder of the ATPasis and lack of mitochondrial complex III ²³¹	BCS1L ²³¹	Aut. rec. and aut. dom. ²³¹	Extremely rare ²³¹		Pilli torti ²³¹	Disorder of the mitochondrial respirasome
Branchio-oculo-facial syndrome (BOFS)	Disorder of the retinoic acid-induced transcription factor AP-2 alpha and thus of the regulation of eye, face, skin, neural tube, and kidney morphogenesis ²³²	TFAP2A ²³² ²³³	Aut. dom. ²³² ²³³	<1:1,000,000 ¹⁷⁵	Symptom-based	Low birth weight and growth and growth retardation, branchial skin alterations (hemangioma-like manifestation at the neck and behind the ears), microphthalmia, ptosis, cataract, dacryocystitis, characteristic facial changes (wide philtrum, cleft lip and palate, flat broad nose, deformed auricles ²³² ²³³	Hearing loss may be conductive, sensorineural or mixed; clinical overlapping with BOR syndrome ²³² ²³³
Branchio-oto-renal syndrome (BOR)	Disorder of the renal formation and the otic placode ²³⁵ ²³⁶ , mild cochlear hypoplasia, second most frequent malformation	EYA1 (40% of the patients with clinical symptoms), SIX1, SIX5 (genes of the EYA-DACH-SIX-PAX pathways) ²³⁴ ²³⁵ ²³⁶	Aut. dom. ²³⁴ ²³⁶	1:40,000 ²³⁴ ²³⁶	Symptom-based	Cervical or preauricular branchial fistula, hypoplasia, dysplasia, or agenesis of the kidneys, aplasia of the 8th cranial nerve ²³⁴ ²³⁶	Variable presentation and severity ²³⁵ , radiologically cochlear hypoplasia ²³⁶
Boudhina-Yedes-Khiari syndrome	Neuro-cutaneous disease ²³⁷	-	Aut. rec. ²³⁷	3 patients worldwide ²³⁷	Symptom-based	Growth retardation, microcephaly, mental retardation, epilepsy and skin lesions ²³⁷
Carpenter syndrome, acrocephalopolysyndactyly type II	Mutation of the guanosin triphosphatase (GTPases) ²³⁸ ²³⁹ ²⁴⁰	RAB23 ²³⁸ ²³⁹ ²⁴⁰	Aut. rec. ²³⁸ ²³⁹ ²⁴⁰	Extremely rare ¹⁷⁵ , about 40 cases are known	Symptom-based	Craniosynostosis, craniofacial malformations, polysyndactyly, obesity, mental disability, hypogonadism ²³⁸ ²³⁹ ²⁴⁰	RAB23=Ras-associated binding protein 23; negative regulator of sonic hedgehog and fibroblast growth factor signalling pathway ²³⁸
CHARGE syndrome, Hall-Hittner syndrome	Neurocristopathy, dysregulated gene expression and development of the neural crest, dysregulation of the neural crest stem cells, dysregulation of the alternative splicing (spliceosomopathy) ⁹⁸ ²⁴¹	CHD7 heterocygotic mutation 8q12 ⁹⁸ as well as newly identified genes: PUF60, EP300, RERE, KMT2D and KDM6A ²⁴¹	Aut. dom. (97% de novo) ⁹⁸ ²⁴¹	0.1–1:10,000 ¹³⁵	Symptom-based, CI	Variable expression of the symptoms, visual loss, cardiac anomalies, skeletal, oronasal, gastrointestinal, and genitourinary malformations, growth disorders, craniofacial malformations, anosmia, facial nerve palsy, immune deficiency ²⁴¹ Diagnostic criteria ⁹⁸ : typical: 2 or 3 main and 2 minor criteria; main criteria: coloboma (ocular), choanal atresia/stenosis, hypo-/aplasia of the semicircular canals; minor criteria: rhomb encephalic dysfunction (brainstem and cranial nerve anomalies), hypothalamo-pituitary dysfunction, malformation of the internal and/or external auditory canal, mediastinal organs (heart, esophagus), intellectual weakness	CHARGE= C oloboma of the eye, H eart defects, A tresia of choanae, R etardation of growth, G enital abnormalities, E ar anomalies; overlapping with Kallmann, Kabuki, 22q11.2 and Nager syndromes as well as with Guion-Almeida mandibulofacial dysostosis ²⁴¹ ; the missing of the semicircular canals is highly predictive for CHD7 mutation
Cockayne syndrome, Neill-Dingwal syndrome	Delayed DNA reparation after UV light exposure, mitochondrial changes ²⁴² ²⁴³	ERCC8, ERCC6 ²⁴²	Aut. rec.	1:250,000 ²⁴²	Symptom-based	Hyposomia, cerebral and retinal atrophy, joint contractures, photosensitivity and wrinkled skin, atherosclerosis and vasculopathy, high blood pressure, stroke and cardiac infarction, peripheral neuropathy ²⁴²	3 types
Coffin-Lowry syndrome	Growth factor regulated serin-threonin-protein kinase ²⁴⁴ ²⁴⁵	RSK2; Locus Xp22.2 ²⁴⁴ ²⁴⁵	X-linked ²⁴⁴ ²⁴⁵	>100 cases are known ²⁴⁴ ²⁴⁵	Symptom-based	Severe mental disability, hyposomia, hypertelorism, prominent front, anteverted nostrils, thick fingers with slim tips, kyphoscoliosis ²⁴⁴ ²⁴⁵
Coffin-Siris syndrome	Mutations of the BRG-1 associated factor (BAF) complex, cell growth, division, replication, and differentiation as well as in DNA reparation ²⁴⁶ ²⁴⁷	ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, SOX11 ²⁴⁶ ²⁴⁷	Aut. dom. and aut. rec. ²⁴⁶ ²⁴⁷	About 100 cases are known ²⁴⁶ ²⁴⁷	Symptom-based	Cognitive and developmental disorder, hypoplastic phalanxes and little finger nails, hirsutism, ptosis, cataract, strabism, hypospadias ²⁴⁶ ²⁴⁷
Cornelia-de-Lange syndrome	Cohesinopathy, disorder of the chromatid cohesion and thus mitosis, disorder of the regulation of the transcription ²⁴⁸ ²⁴⁹ ²⁵⁰	SMC1A, SMC3, RAD21 or HDAC8 ²⁴⁸ ²⁴⁹ ²⁵⁰	Aut. dom. or X-linked	More than 400 cases are known	Symptom-based	Facial dysmorphy (arched eyebrows with synophrys, long philtrum, thin lips, hairy front), prenatal and postnatal growth retardation, cognitive impairment, gastrointestinal malformations, congenital cardiac anomalies and malformed extremities ²⁴⁸ ²⁴⁹ ²⁵⁰
Curschmann-Batten-Steinert syndrome, myotonal dystrophy	Gene defect resulting in splicing defects of the pre-mRNAs of multiple genes	DMPK (type I), CNBP (type II); both loci adjacent to the DFNA18 locus ²⁵¹ ²⁵² ²⁵³	Aut. dom.			Myotonia, muscular atrophy, insulin resistance, cardiac arrhythmia, cataract, cognition disorder and mental disability	Two types are known, also subclinically cochlear damage without hearing loss
Donnai-Barrow syndrome	Occulo-auditory syndrome ²⁵⁴ ²⁵⁵	LRP2 ²⁵⁴ ²⁵⁵	Aut rec. ²⁵⁴ ²⁵⁵	<50 patients worldwide ²⁵⁴ ²⁵⁵	Symptom-based	Diaphragmatic hernia, exophthalmos, missing corpus callosum, myopia, proteinuria ²⁵⁴ ²⁵⁵
DOOR syndrome	Unknown	TBC1D24 ²⁵⁶ , SMARCB1 ²⁵⁷	Aut. rec. ²⁵⁶ ²⁵⁷	About 50 cases are known ²⁵⁷	Symptom-based	Onychodystrophy, osteodystrophy, retardation, seizures ²⁵⁶ ²⁵⁷	DOOR=deafness, onychodystrophie, osteodystrophie, retardierung ²⁵⁶ ²⁵⁷
Ehlers-Danlos syndrome	Disorder of the collagen biosynthesis ²⁵⁸ ²⁵⁹	B4GALT7, B3GALT6, SLC39A13 and others ²⁵⁹	Aut. rec.	1:5,000 ²⁵⁸	Symptom-based	Skin and joint hyperlaxity, spondylodysplasia, kyphoscoliosis, aneurysms and ruptures of arteries, osteopenia/osteoporosis ²⁵⁸ ²⁵⁹	Different subtypes are known
Fountain syndrome	unknown	Unknown	Aut. rec.	Extremely rare	Symptom-based	Mental retardation, erythematous swelling of the face, skeletal changes ²⁶⁰
Freeman-Burian (Sheldon) syndrome	Distal arthrogryposis, multiple contractures ²⁶¹	MYH3 ²⁶¹	Sporadic, aut. dom. ²⁶¹	About 100 cases are known	Symptom-based	Microstomia, pursed lips just as for siffling, H- or V-shaped chin defect, prominent nasolabial fold and major contractures of 2 or more body regions, typically hands and feet ²⁶¹	Craniofacial syndrome
Hajdu-Cheney syndrome	Disorder of the intercellular notch signaling pathway ²⁶²	NOTCH2 ²⁶²	Aut. dom.	More than 80 cases are known ²⁶²	Symptom-based	Craniofacial anomalies, cardiovascular disease, kidney cysts ²⁶²	Craniofacial syndrome
HOXA1 syndrome	Developmental disorders of the head, the neural system, the inner ear, and the vestibular system ²⁶³	HOXA1 ²⁶³	Aut. rec. ²⁶³	Extremely rare ²⁶³		Bilateral duane syndrome, cerebrovascular and cardiovascular malformations, autism, variable phenotypes are possible ²⁶³	Mixed hearing loss
Hutchinson-Gilford-Progerie syndrome	Reduced subcutaneous fat, aberrant lamin A production ²⁶⁴	LMNA ²⁶⁴	de novo, Aut. dom. ²⁶⁴	1:4,000,000 ²⁶⁴		Osteolysis, delayed eruption and loss of milk teeth, abnormal skin pigmentation, alopecia, osteoporosis, severe atherosclerosis, nightly lagophthalmos ²⁶⁴
Johanson-Blizzard syndrome	Defect of ubiquitin protein ligase E3 components N-rekognin1 (UBR1) and thus disturbed ubiquitination and degradation of ubiquitin-associated proteins, disorder of the cell proliferation, differentiation, and apoptosis ²⁶⁵	UBR1 ²⁶⁵	Aut. rec. ²⁶⁵	Very rare, about 70 cases are known ²⁶⁵		Exocrine pancreas insufficiency, hypoplasia of the nasal alae, oligodontia, skull defects, cognitive disorder, hyposomia, hypothyroidism, microcephaly, intrauterine growth disorder, congenital heart defect, urogenital and anorectal malformations kidney anomaly, late-onset diabetes mellitus ²⁶⁵
Juberg-Marsidi syndrome	Disorder of the E3 ubiquitin ligase regulating the key factors such as p53 and Mcl1 ²⁶⁶	HUWE1 ²⁶⁶	X-linked, rec. ²⁶⁶	6 families are known ²⁶⁶	Symptom-based	Mental retardation, growth disorder, hypogonadism, hypertelorism, microcephaly ²⁶⁶	Hearing loss, possibly due to recurrent otitis media?
Kabuki syndrome	Disturbed histones-lysine methylation and chromatin remodeling ²⁶⁷	KMT2D, sometimes also KDM6A ²⁶⁷	X-linked ²⁶⁷	1:32,000–86,000 ²⁶⁷		Newborn hypotonia, nutritional problems in infants and toddlers, postnatal growth disorders, skeletal anomalies, disorders of the immune system, endocrine anomalies and congenital malformations of the heart, kidney, and palate ²⁶⁷
Kallmann syndrome	Defect development of gonadotropin-releasing hormone secreting neurons and absence of puberty ²⁶⁸	SOX10, KAL1, FGFR1, FGF8, FGF17, CHD7 and others ²⁶⁸	X-linked, aut. rec. or aut. dom.	Very rare	Hormone replacement therapy	Hypogonadotropic hypogonadism with anosmia, cleft lip and palate, renal agenesis, short metacarpal bones, synkinesis, movement disorders of the eyes, cerebellar ataxia, and scoliosis ²⁶⁸	Incidence of the congenital hypogonadotropic hypogonadism syndrome: 1:50,000
Kearns-Sayre syndrome	Mitochondiopathy, disorder of the oxidative phosphorylation ²⁶⁹	Deletion of the mitochondrial DNA ²⁶⁹	de novo, rarely X-linked ²⁶⁹	1.6:100,000 ²⁶⁹		Chronic progressive external ophthalmoplegia, retinopathia pigmentosa, disorders of stimuli conduction, endocrine involvement, weakness of non-ocular muscles, encephalopathy ²⁶⁹ ²⁷⁰	Characteristic triad: disease onset before the age of 20, chronic-progressive external ophthalmoplegia, retinopathia pigmentosa ²⁶⁹
Klippel-Feil syndrome	Congenital synostosis ²⁷¹	Different, GDF6, GDF3, MEOX1	Sporadic, sometimes aut. rec. or aut. dom.	1:40,000 ²⁷¹		Congenital malformation of the spine, extraskeletal manifestation with urogenital and cardiovascular anomalies, neural tube defects and cleft palate ²⁷¹ ²⁷²
Kniest dysplasia	Type II collagenosis ²⁷³	COL2A1 ²⁷³	Aut. dom.	Rare, exact incidence is unknown ²⁷³		Short torso and extremities, kyphoscoliosis and craniofacial anomalies ²⁷³
LADD syndrome		FGFR2, FGFR3, FGF10 ²⁷⁴		Very rare, less than 30 cases are known ²⁷⁴		Hypoplasia/aplasia of the lacrimal glands/duct, hypoplasia/aplasia of the salivary glands, dental anomalies, malformation of the ears and fingers ²⁷⁴
Landau-Kleffner syndrome	Acquired epileptiform aphasia ²⁷⁵	Unclear, mutation of GRIN2A, RELN, BSN, EPHB2, and NID2 have been described ²⁷⁵	No data in the literature ²⁷⁵	About 1:1,000,000 ²⁷⁵	Anticonvulsants, steroids, adrenocorticotropic hormone replacement diet, immunoglobulins ²⁷⁵	Epileptic seizures, regression of speech, aggressive and hyperactive behavior ²⁷⁵	Abnormal EEG, autism spectrum disorders
Noonan syndrome (formerly: LEOPARD syndrome)	RAS/MAPK disorders, developmental disorder of the neural crest due to mutations of the “non-receptor protein tyrosine phosphatase” SHP2 ²⁷⁶	PTPN11, RAF, and BRAF ²⁷⁶	Aut. dom.	About 200 cases are known ²⁷⁶		Lentigines, abnormal ECG, ocular hypertelorism, pulmonary valve stenoses, micrognathia, growth retardation ²⁷⁶
Levy-Yeboa syndrome		KCNQ1 and KCNE3 ²⁷⁷	Aut. rec.	1 family with 3 siblings has been described ²⁷⁷		Congenital myopathy, recurrent secretory diarrhea, epidermolysis bullosa, microcephaly ²⁷⁷
Marshall syndrome	Disturbed ectodermal development ²⁷⁸	Coll11A1 ²⁷⁸	Aut. dom.		<1:1,000,000	Facial dysmorphia, hypoplasia of the nasal bone and frontal sinus, skeletal anomalies ²⁷⁸	Progressive hearing loss
Maternally Inherited Leigh Syndrome (MILS) and NARP syndrome	Mitochondrial disease ²⁷⁹	MTATP6 ²⁷⁹	Maternal ²⁷⁹		1:12,000–1:40,000	Neuropathy, ataxia, retinitis pigmentosa ²⁷⁹	MILS 90% Mt DNA mutated; NARP 70–80% Mt DNA mutated; Rawle et al.
Mayer-Rokitansky-Küster-Hauser syndrome	Inhibition malformation of Müller’s ducts	-	-		1:4,000–1:5000 ²⁸⁰	Ovarian and uterine agenesis, renal dysplasia ²⁸⁰
McCune-Albright syndrome	Overproduction of growth factors and hormones ²⁸¹	GNAS ²⁸¹	Mosaic ²⁸¹		1:100,000–1:1,000,000	Fibrous dysplasia, Café-au-lait stains, pituitary dysfunction ²⁸¹
MELAS syndrome	Mitochondrial disease ²⁸² ²⁸³	MT-TL1 and further mitochondrial DNA mutations ²⁸² ²⁸³	Maternal			Myopathy, encephalopathy and stroke-like episodes, lactate acidosis ²⁸² ²⁸³	Pathological changes in the stria vascularis, confirmed post mortem
MERRF	Mitochondrial disease ²⁸⁴	MT-TK ²⁸⁴	Maternal ²⁸⁴			Myoclonus, epileptic seizures, ataxia, muscular weakness and dementia, hyposomia, degeneration of the optic nerve, peripheral neuropathy, cardiomyopathy ²⁸⁴
Moebius syndrome	Disorder of the brainstem development ²⁸⁵	REV3L, PLXND1 ²⁸⁵	De novo	1:250,000 ²⁸⁵		Facial nerve palsy as well as paresis of other cranial nerves	Hearing loss in about 10% of the patients
Myhre syndrome	“gain of function” mutation, excessive TGF beta signaling ²⁸⁶	SMAD4 ²⁸⁶	Aut. dom. ²⁸⁶	<1:1,000,000		Microcephaly, midfacial hypoplasia, prognathia and blepharophimosis, hyposomia ²⁸⁶	Enlarged vestibular aqueduct as most frequent radiological finding
Otosponylomegaepiphyseal dysplasia, OSMED syndrome	Collagen defect ²⁸⁷	COLL11A2 ²⁸⁷	Aut. rec. ²⁸⁷	<1:1,000,000 ²⁸⁷		Enlarged epiphyses, skeletal dysplasia with relatively short extremities, vertebral anomalies ²⁸⁷	High-frequency hearing loss, Pierre Robin sequence
Pendred syndrome	Partial disorder of the pendrin, an anion exchanger	SLC26A4, FOX11, KCNJ10 ²⁸⁸	Aut. rec. ²⁸⁸	7:100,000 ²⁸⁸		Anomalies of the temporal bone with dilated vestibular aqueduct and sometimes hypoplastic cochlea, vertigo, euthyroid goiter ²⁸⁸ ²⁸⁹	Also hypothyroid coursed
Pfeiffer syndrome	Prolonged FGF signaling ²⁹⁰	FGFR1, FGFR2 ²⁹⁰	Aut. dom. ²⁹⁰	1:100,000 ²⁹⁰		Craniosynostoses ²⁹⁰	Conductive hearing loss and sometimes also inner ear hearing loss
PIGA syndrome	Glycosyl phosphatidylinositol deficiency ²⁹¹	PIGA ²⁹¹	X-linked ²⁹¹	Rare ²⁹¹		Infantile spasms, epilepsy, mental retardation, cerebral lesions ²⁹¹
Primary ciliary dyskinesia (Kartagener syndrome)		DNAI1, DNAH5 DNAH11, CCDC39, CCDC40 ²⁹²	Aut. rec. ²⁹²	1:16,000 ²⁹²		Daily cough, chronic infection of the airways, situs inversus, asplenia, infertility ²⁹²	Otitis media, inner ear hearing loss (30%)
Jervell-Lange-Nielsen syndrome	Ion channel mutation ²⁹³	KCNE1 oder KCNQ1, SCN5A ²⁹³	Aut. rec. or aut. dom.	1:2,000–1:44,500	Defibrillator, beta blocker, CI	Cardiac arrhythmia, prolonged QT interval ²⁹³
Rieger-Axenfeld syndrome	Irido-dental dysplasia ²⁹⁴	FOXC1 8294]	Aut. dom.	1–9:1,000,000		Malformations of the face, teeth, umbilicum, and skeleton, congenital heart defect ²⁹⁴
Russel-Silver syndrome	Methylation disorder/imprinting disorder ²⁹⁵	-	Aut. dom., Aut. rec. ²⁹⁵	1:15,000 ²⁹⁵		Developmental retardation, hyposomia, clinodactyly, hypoglycemia, scoliosis ²⁹⁵
Schinzel-Giedion syndrome	“Gain of function” mutation ²⁹⁶	SETBP1 ²⁹⁶	Aut. dom. ²⁹⁶	<1:1,000,000 ²⁹⁶		Facial dysmorphia, hydronephrosis, severe developmental delay, mental retardation as well as genital and cardiac anomalies, increased incidence of neuroepithelial dysplasia 8296]
Senior Løken syndrome	Ciliopathy ²⁹⁷ ²⁹⁸	More than 10 genes ²⁹⁸	Aut. rec. ²⁹⁷	1:1,000,000 ²⁹⁷	Symptom-based	Nephronopthysis, retinopathy, diabetes insipidus, cerebellar ataxia, hepatic fibrosis ²⁹⁷ ²⁹⁸
SeSAME syndrome	Disturbed development of the brain, kidneys, and stria vascularis ²⁹⁹	KCNJ10 ²⁹⁹	Aut. rec. ²⁹⁹	<1:100,000 ²⁹⁹		Epilepsy, ataxia, and electrolyte disorder ²⁹⁹	Synonym: EAST syndrome
Sotos syndrome	Mutation of the histon methyltransferase ³⁰⁰	NSD1 ³⁰⁰	Aut. dom. ³⁰⁰	1:10,000 ³⁰⁰		Long, narrow face, high front, red cheeks and small pointed chin, ADHS, hypotension, excessive growth ³⁰⁰	Also conductive hearing loss ³⁰⁰
STAR syndrome	Unknown ³⁰¹	FAM58A (CCNQ) ³⁰¹	X-linked ³⁰¹	Rare ³⁰¹		Telecanthus, syndactyly, renal and anogenital malformations ³⁰¹
Tietz syndrome	Disturbed development of melanocytes ³⁰²	MITF ³⁰²	Aut. dom.	<50 patients worldwide	CI	Hypopigmentation and high-grade hearing loss ³⁰²	Also in Waardenburg syndrome
Townes-Brocks syndrome	Malformation of the cilia ³⁰³	SALL1 ³⁰³	Aut. dom. ³⁰³	-		Anal atresia, dysplastic ears and malformation of the thumbs ³⁰³
Usher syndrome	Degeneration of hair cells and photoreceptors ³⁰⁴	Ush 1: MYOVIIA, CDH23, PCDH15, SANS Ush2: ADGRV1, WHRN Ush3: CLRN1 ²⁸⁸ ³⁰⁴	Aut. rec. ³⁰⁴	3:100,000 ³⁰⁴	CI	Ush 1: congenital hearing and balance disorder, visual loss before puberty Ush 2: congenital hearing loss, visual loss after puberty Ush 3: progressive hearing loss, variable visual loss and balance disorder ²⁸⁸ ³⁰⁴	10% of all hearing disorders in children
Vici syndrome	Global developmental disorder ³⁰⁵	EPG5 ³⁰⁵	Aut. rec. ³⁰⁵	100 patients worldwide ³⁰⁵	Symptom-based ³⁰⁵	Agenesis of the corpus callosum, cataract, oculocutaneous hypopigmentation, combined immune deficiency ³⁰⁵	Disorder of autophagy
Waardenburg syndrome	Disturbed development of melanocytes	Pax 3 (type I, III) MITF, SNAI2 (type II) Sox10, EDN3, EDNRB (type IV) ²⁸⁸ ³⁰⁶	Aut. dom. (I, III) Aut. rec. (II, IV)	1:40,000	CI ³⁰⁷	Hypopigmentation and hearing loss (type II)+dystopia canthorum (type I)+malformations of the upper extremities (type III)+Hirschsprung’s disease (type IV) ²⁸⁸ ³⁰⁶	Asymmetric and variable hearing loss
Wolfram syndrome, DIDMOAD	Mitochondrial disorder due to disturbed calcium homeostasis and stress in the endoplasmatic reticulum ³⁰⁸ ³⁰⁹	WFS2, WFS2 ³⁰⁸ ³⁰⁹	Aut. rec. ³⁰⁸ ³⁰⁹	1:55,000 ³⁰⁸ ³⁰⁹	Insuline	D iabetes i nsipidus, d iabetes m ellitus, o pticus a trophy and d eafness (DIDMOAD)	Progressive hearing loss as of childhood, neurological symptoms
Zellweger spectrum diseases	Peroxisomal functional loss ³¹⁰	Pex 1,6,10 ³¹⁰	Aut. rec. ³¹⁰	1:50,000 ³¹⁰	Bile acid ³¹⁰	Flat face, renal and hepatic insufficiency, retinitis pigmentosa ³¹⁰	Auditory neuropathy, infant-refsum disease
Neural/central
Alternating hemiplegia of childhood (AHC), Weber syndrome, medial medullar syndrome	Channelopathy, alpha3 subunit of Na+/K+ATPase (exclusively expressed in neurons of the CNS)	ATP1A3	De novo mutations, rarely aut. dom.	1:1,000,000 ¹³⁵	Symptom-based	Episodes of weakness or paresis, choreoathetosis, dystonia, dyspnea, ataxia, dysfunction of the autonomous neural system, psychomotor regression, episodic nystagmus ¹³⁵
Arnold-Chiari malformation	Syringomyelia, developmental disorder of the brainstem and the upper medulla ³¹¹	Unknown	Unknown	Unknown	Symptom-based	Occipital cephalgia, diplopy, photophobia, spina bifida, meningocephaloceles, dysphagia, dysarthria, sleep apnea ³¹¹	Type 0-VI
Autosomal dominant hereditary ataxia	Spinocerebellar degeneration, different types are known ³¹²	Different genes	Aut. dom., X-linked	1–5:100,000	Symptom-based	Ataxia, disturbed hand-eye coordination, speech disorders, nystagmus, diplopia, cognitive impairment, opticus atrophy, retinitis pigmentosa, opthalmoplegia, diabetes, cardiac and skeletal diseases ³¹²
Canavan-Van Bogaert-Bertrand	Leukodystropia, asparto-acylase enzyme deficiency and accumulation of N-acetyl aspartate acid ³¹³ , diffuse spongiform of the white brain substance, dys- and demyelination ³¹⁴	ASPA ³¹³ ³¹⁴	Aut. rec. ³¹³ ³¹⁴	1:100,000, more frequently in Ashkenasim ¹⁷⁵	Symtpom-based, experimental gene and cell therapy, experimental approaches tested in humans with lithium	Macrocephaly, muscular weakness, dysphagia, seizures, nasal regurgitation, opticus atophy, severe progressive psychomotor retardation	Auditory neuropathy ³¹⁴ , cases without auditory neuropathy and post mortem confirmation of hair cell loss ³¹⁵ , congenital, infantile, and juvenile types are described
CAPOS/CAOS	Channelopathy, alpha3 subunit of Na+/K+ATPase (exclusively expressed in neurons of the CNS)	ATP1A3 c.2452G>A ³¹⁶	De novo mutation and aut. dom. ³¹⁶	<1:1,000,000 ¹⁷⁵ , slightly more than 40 patients are described in the literature ³¹⁷	Symptom-based	Cerebellar ataxia, areflexia, pes cavus, opticus atrophy ³¹⁶ ³¹⁸
Charco-Marie-Tooth neuropathy	CMT with hearing loss ³¹⁹	Different genes: ABDH12; AIFM1; DNMT1; PRPS1; PTRH2 ³¹⁹	Aut. rec., dom., X-linked ³¹⁹	1:3,300 ³¹⁹	Symptom-based ³¹⁹	Progressive neuropathy, muscular weakness, paralysis of the vocal folds, retinitis pigmentosa and cataracts, mental disability with dementia ³¹⁹	80 genes; classification according to the genotype; mild to severe hearing loss, “hidden hearing loss”
(Stilling-Türk-)Duane syndrome	Cranial dysinnervation ³²⁰ ³²¹	CHN1, MAFB, HOXA1, CDH2 ³²⁰ ³²¹	Aut. dom. and aut. rec. ³²⁰ ³²¹	1:1,000 ³²⁰ ³²¹	Symptom-based	Limited horizontal eye movement, abducens hypoplasia, skeletal, auricular, ocular, neural, and renal anomalies ³²⁰ ³²¹	3 types are known, sometimes conductive hearing loss ³²¹
Hereditary sensory neuropathy	Axonal atrophy and degeneration of the sensory neurons, disturbed sphingo-lipid synthesis [322m 323]	SPTLC1 ³²² ³²³	Aut. dom. ³²² ³²³	2:1,000,000		Loss of distal sensorics, painless injuries, skin ulcer, bone infections, partly severe infections requiring amputations of toes or feet ³²² ³²³ , dementia	Extensive microglia activation that may also be classified as inflammatory or metabolic
Superficial siderosis	Hemosiderin deposit as consequence of recurrent bleeding in the subarachnoidal space	-	-	1:1,000,000 ³²⁴	Deferiprone, CI ³²⁴	Progressive bilateral hearing loss, ataxia, vestibular dysfunction, myelopathy with pyramidal signs ³²⁴
Others
Cochlear dehiscence (“Third window” syndrome)	Dilated cochlear and vestibular aqueduct, bone dehiscence ³²⁵				Surgery	Pseudo conductive hearing loss, vertigo (noise- or Valsalva-induced), autophonia ³²⁵
Intralabyrinthine schwannoma	Neoplasm			1:100,000 ³²⁶	Surgery ³²⁷ , CI ³²⁸	Hearing loss, slowly progressive or fluctuating, vertigo, unsteady gait ³²⁷
Progressive myoclonal epilepsy	Group of disorders with common symptoms; comprises genetic diseases, mitochondrial diseases, and metabolic syndromes ³²⁹	-	-	-	-	Myoclonus, epilepsy, neurodegeneration ³²⁹