SOFT syndrome with Kohlschutter–Tonz syndrome

ABSTRACT

We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling. Rhizo-mesomelic dwarfism was detected antenatally. Within 24 hours of birth, he developed multiple seizures. Examination revealed severe short stature, dolichocephaly, broad forehead, deep set eyes, low set ears, bulbous nose, small, irregular teeth, pointed chin, and triangular facies. He had rhizomelic shortening, stubby fingers, pes planus, and scanty hair. Neurological evaluation revealed ataxia, hypotonia, and global developmental delay. Skeletal survey radiograph revealed shallow acetabuli, short femurs and humerus, short, broad metacarpals and short cone-shaped phalanges with cupping of phalangeal bases. Clinical exome analysis revealed homozygous mutations involving the POC1A gene and the SLC13A5 gene responsible for SOFT syndrome and Kohlschutter-Tonz syndrome respectively, which were inherited from the parents. Both these syndromes are extremely rare, and their co-occurrence is being reported for the first time.

Introduction

A rare but important cause of short stature is the presence of a genetic syndrome. Consanguinity increases the risk of such autosomal recessively inherited syndromes. We report a child with short stature–onychodysplasia–facial dysmorphism–hypotrichosis (SOFT) syndrome and Kohlschutter–Tonz syndrome (KTS), two extremely rare disorders, with co-occurrence reported for the first time in literature.

Case Report

A 2.2-year-old boy, the second of three siblings, born to parents with second-degree consanguinity presented to our Pediatric Endocrinology Unit for the evaluation of short stature. The first sibling delivered at 32 weeks had short limbs with deformities and died within four hours of birth.

The mother’s age at second conception was 25 years. Serial ultrasounds suggested rhizo-mesomelic dwarfism. Anomaly scan at 18 weeks revealed long bone lengths (femur, humerus, tibia, and ulna) below the 5^th percentile without axial skeletal abnormalities, bowing, and with normal mineralization. The child was delivered at term and weighed 3.2 kg. Despite no perinatal asphyxia or injury, he developed multiple seizures within 24 hours and received levetiracetam (50 mg/kg/day) and lacosamide (8 mg/kg/day). After a year of therapy, he was well-controlled, with the last seizure being one year ago.

At 2.2 years, his length was 71.0 cm (-5.4 Z-score), weight was 6.9 kg (-4.8 Z-score), and head circumference was 45.5 cm (-2.1 Z-score). Mid-parental height was 168 cm; he was growing far below (-4.7 Z-score) his target height centiles. Physical examination revealed dolichocephaly, broad forehead, deep-set eyes, low-set, posteriorly rotated ears, bulbous nose, small, irregularly positioned teeth, pointed chin, and triangular facies [Figure 1]. He had short limbs (rhizomelic shortening), an upper: lower segment ratio of 1.7:1, stubby fingers, normal nails, and scanty hair. Neurological examination revealed ataxia and hypotonia; other systemic examinations were normal. He had global developmental delay (could sit or stand only transiently and monosyllable speech) with relatively better social milestones.

Figure 1.

Clinical photographs depicting dolichocephaly, broad forehead, low-set and posteriorly rotated ears, prominent helix and antihelix, bulbous nose, pointed chin, scanty hair, small and irregularly positioned cylindrical teeth with wide interdental spaces, and rhizomelic shortening of limbs and pes planus

Echocardiography in infancy showed a small patent ductus arteriosus (PDA) with mild tricuspid regurgitation. The electroencephalogram revealed sharp, slow-wave discharges over the posterior regions. The hemogram, 25-hydroxycholecalciferol, and thyroid profile were normal. Skeletal X-rays revealed shallow acetabuli, short femurs and humerus, short, broad metacarpals, and cone-shaped phalanges with basal cupping [Figure 2]. Bone age (Tanner–Whitehouse 3 method) was delayed by a year.

Figure 2.

Skeletal survey radiographs depicting shallow acetabuli, short femurs and humerus, short and broad metacarpals, and short cone-shaped phalanges with cupping of the phalangeal bases

Clinical exome analysis revealed a pathogenic homozygous two-base pair deletion in exon 7 of the POC1 centriolar protein A (POC1A) gene, causing a frameshift and premature truncation of the protein, 25 amino acids downstream to codon 267 (p.Leu267ProfsTer25). Another homozygous missense mutation was observed in exon 11 of the solute carrier family 13, member 5 (SLC13A5) gene, causing the substitution of methionine by isoleucine at codon 525, pathogenic for early-onset epileptic encephalopathy 25. Both parents were heterozygous carriers of both mutations [Figure 3].

Figure 3.

Sequence chromatograms showing variation in exon 7 of the POC1A gene (chr3:g.52138181_52138182del; c.800_801del; p.Leu267ProfsTer25) and variation in exon 11 of the SLC13A5 gene (chr17:g.6687529C > G; c.1575G > C; p.Met525Ile) detected in heterozygous condition in the father (top images) and mother (bottom images) of the index case

Levetiracetam (50 mg/kg/day) and lacosamide (11 mg/kg/day) were continued. The child had grown 2 cm in length at a follow-up visit after 8 months.

Discussion

SOFT syndrome, first described by Shalev, is a rare primordial dwarfism caused by homozygous or compound heterozygous POC1A gene mutations, comprising Short stature, Onychodysplasia, Facial dysmorphisms and hypoTrichosis.[1,2] Although the exact pathogenesis is unclear, centrosome disorganization and disordered trafficking from the plasma membrane to the Golgi apparatus have been demonstrated in affected individuals.[2]

Growth retardation beginning early in the second trimester has been documented.[1,3] Most patients have been small for gestational age.[1,2,4] In contrast, our patient weighed normal at birth, but showed evidence of poor intrauterine length. Short stature, a hallmark of SOFT syndrome, may be proportionate or with rhizo-mesomelic limb shortening.[4] Most patients respond poorly to recombinant growth hormone (GH), with an adult height equivalent to a 6- to 8-year-old child.[1,2] GH administration may lead to the development of metabolic syndrome in these children.[5] Relative macrocephaly prevails in early childhood with profound microcephaly in adulthood.[1,6] Our patient was microcephalic even in childhood. Majority exhibit normal development and intelligence, contrary to our patient.[1,6] This may be explained by cerebral damage following repeated seizures in infancy, coupled with hypotonia and ataxia as a part of epileptic encephalopathy, causing global developmental delay.

Typical dysmorphisms reported are triangular face, dolichocephaly, sparse hair, and crowded teeth.[1,2,6] Ectodermal changes such as hypoplastic nails are frequent, but were absent in our patient.[2,4] Metaphyseal irregularities involving long bones, hypoplastic pelvis, cone-shaped epiphyses, delayed carpal, and vertebral ossification are consistently observed, with alleviation of dysplasia as age progresses.[1,3,6]

Rarely, cardiac anomalies have been reported. Chen and Al-Kindi et al. reported the presence of PDA, and Li et al. reported tricuspid regurgitation, both being detected in our patient.[2,4,5] Shaheen et al.[6] observed profound developmental delay and hypotonia in a 6-year-old child with SOFT syndrome. Whether the hypotonia in our patient was due to SOFT syndrome or in combination with epileptic encephalopathy remains speculative.

Early-onset epileptic encephalopathies present as severe, recalcitrant seizures, often with developmental delay. The SLC13A5 gene encodes a sodium-dependent citrate transporter required for neuronal uptake of citrate.[7] Enamel hypoplasia and hypodontia have been reported in several patients with SLC13A5 mutations.[7,8] KTS is an extremely rare disorder with early-onset epilepsy, intellectual disability, spasticity, and amelogenesis imperfecta. First, reported due to mutations in the rogdi atypical leucine zipper (ROGD-I) gene, it is now also reported due to biallelic mutations in SLC13A5.[9]

Seizure onset in the early neonatal period is the most common presentation.[8,9] Though often recalcitrant, a spectrum of severity exists, with good seizure control in a few as they grow older, akin to our patient. However, seizure control is not associated with good neuro-outcomes. Most patients develop profound developmental delay and locomotor abnormalities irrespective of seizure frequency.[8,9,10] Majority present with infantile ataxia and hypotonia, progressing to incapacitating spasticity and dystonia later in life.

Amelogenesis imperfecta has been consistently observed in KTS.[7,9] Enamel hypoplasia is reported, causing pitting and brown discoloration. Smooth, small, cylindrical teeth, wide interdental spaces, and dental chipping have been reported, similar to our patient.[8,9] Among eight patients with SLC13A5-associated epilepsy, Hardies et al.[7] observed dental hypoplasia or hypodontia in all patients.

KTS has an overall poor prognosis due to severe physical and intellectual incapacitation. Deaths have been reported during childhood.[7] Arvio et al.[10] reported siblings (56-year-old sister and 54-year-old brother) with SLC13A5-related severe childhood epilepsy, requiring institutional care for spasticity, profound intellectual disability, autism, and dental erosions despite being seizure-free for 20 years.

Our study is the first reported case of co-occurrence of SOFT and KTS. Consanguinity increases the chances of co-occurrence and may worsen clinical outcomes.

Declaration of patient consent

The authors certify that appropriate patient consent was obtained.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.