Commonly Associated Disorders with Complete Scalp Alopecia in Early Childhood: A Review

ABSTRACT

Complete scalp hair loss can be a source of distress for affected children and their families. In addition to infectious and trauma-related causes of hair loss, infants and children may present with total scalp alopecia arising from a range of genetic predispositions. Our objective with this review was to identify the common genetic conditions in children with complete scalp alopecia. The PubMed Database was reviewed for all articles from 1962 to 2019 containing the search terms related to genetic alopecia. The conditions with at least five reported cases in the literature were considered for the inclusion. All clinical trials, retrospective studies, and cases on human subjects and written in English were included. Six genetic conditions related to complete scalp alopecia were included in this review. The most common genetic conditions associated with total scalp hair loss include: alopecia totalis/Alopecia universalis (AU), atrichia with papular lesions, AU congenita, hereditary Vitamin D-resistant rickets type IIA, alopecia with mental retardation, and pure hair and nail ectodermal dysplasia. In children presenting with total scalp hair loss, a myriad of genetic and environmental factors may be the underlying cause. Increased awareness of potential genetic conditions associated with total scalp hair loss may assist in diagnosis, with improved the prognosis for the children.

INTRODUCTION

Complete alopecia of the scalp can be a presentation of certain autoimmune or genetic conditions presenting in infancy and childhood. Each child may present uniquely based differential manifestations of disease onset, pattern, location, and symptomology. The common causes of extensive scalp alopecia include tinea infections, traction alopecia, trichotillomania, or telogen effluvium. However, due to the high disease burden and adverse effects of quality of life from hair loss, additional etiologies such as genetic disorders should also be considered.[1]

In order to aid the physicians in managing children with complete alopecia of a scalp, we aim to review the clinical presentation, pathogenesis, diagnosis, and treatment options for the genetic conditions most commonly associated with complete scalp alopecia in the literature.

MATERIALS AND METHODS

A primary literature search was conducted from 1962 to 2019 using the PubMed database. This search sought to identify the genetic causes of alopecia. The terms, “genetic OR gene OR locus OR heritable OR inheritance OR variant OR mutation” AND “complete OR total” AND “scalp alopecia” were used. Given the vast literature on genetic conditions associated with alopecia our review focused on genetic conditions associated with complete alopecia of the scalp in children. The inclusion criteria included genetic conditions with at least five cases noted in the literature, English language, and human subjects; with all clinical trials, retrospective studies, and cases included. Genetic conditions with prominent musculoskeletal abnormalities were excluded, as these children typically do not seek a diagnosis based on total scalp alopecia alone. An exception was made for Hereditary Vitamin D-Resistant Rickets (HVDRRs), which may present with alopecia prior to skeletal findings.

RESULTS

A total of 231 studies on six genetic conditions associated with total scalp alopecia were reviewed. The most commonly reported condition was Alopecia totalis/Alopecia universalis (AT/AU), with 103 case reports and clinical trials. In addition, 58 studies on atrichia with papular lesions (APLs) and Alopecia universalis congenita (AUC) combined, 53 manuscripts on for HVDRR type IIA, 12 studies on pure hair and nail ectodermal dysplasia (PHNED), and five manuscripts on alopecia with mental retardation alopecia-mental retardation syndrome (APMR) were found [Table 1]. Given the rarity of these conditions, a majority of the cases were reported in case reports or case series.

Table 1.

Clinical and genetic characteristics of the most common causes of total scalp alopecia in early childhood

Condition	Approximate frequency/case reports	Onset	Locus	Gene	Pattern of inheritance	Hair defects	Nonhair defects	Diagnostic tools
AT and AU	1 in 10,000-20,000	Varies (alopecia areata average age of onset~6 years old)	6p21.32 6p21.33 18p11 2q14.1 9q33.2a	HLA-DQB1 MICA PTPN2 IL1RN TRAF1/C51	Mu	Total scalp alopecia +/− body alopecia	Nail dystrophy (10%-20% of patients)	Biopsy; trichoscopy
APL	~60	Birth or first few weeks of life	8p12	HR	AR	Irreversible alopecia of scalp, eyebrow, axillary, and pubic hair; absent to sparse eyelashes	Keratin-filled, milia-like papules	Genetic testing; clinical criteria
AUC	~30						N/A	Genetic testing; clinical criteria
HVDRR with alopecia	~100	First few months of life	12q13.1	VDR	AR	Sparse to complete scalp alopecia	Osteomalacia; bowed legs; dental defects; muscle weakness; convulsions; skin papules	Genetic testing; lab abnormalities; elevated calcitriol, hypocalcemia, hyperparathyroidism, hypophosphatemia Elevated alkaline phosphatase
PHNED	~20	Birth	12q13.13 12q13.13–12q14.3	KRT85 HOXC13	AR	Hypotrichosis or complete scalp alopecia	Nail dystrophy	Biopsy; clinical criteria
APMR	<20	Birth	3q26.33–q27.3 21q22.3 3q26.2-q26.31, 18q11.2-q12.2, 1p31.1-p22.3, 8p23.1, 8p22-p21.3, 14q24.3-q31.3	AHSG LSS Other	AR	Complete scalp alopecia	Mild-to-severe intellectual disability; variable epilepsy, microcephaly, developmental delay, and hypogonadism	Genetic testing; clinical criteria

^aNot a complete list. Please see Lee (2013) for further genetic findings associated with alopecia areata. HLA-DQB1 - Human leukocyte antigen-DQB1; MICA - MHC Class I polypeptide-related sequence A; PTPN2 - Protein tyrosine phosphatase nonreceptor type 2; IL1RN - Interleukin 1 receptor antagonist; TRAF1/C5 - TNF receptor-associated factor 1/C5; HR - Hairless; VDR - Vitamin D receptor; KRT85 - Keratin 85; HOXC13 - Homeobox C13; AHSG - Alpha-2-HS-glycoprotein; Mu - Multifactorial; AR - Autosomal recessive; LSS - Lanosterol synthase; AT - Alopecia totalis; AU - Alopecia universalis; APL - Atrichia with papular lesions; AUC - Alopecia universalis congenita; HVDRR - Hereditary vitamin D-resistant rickets; PHNED - Pure hair and nail ectodermal dysplasia; APMR - Alopecia-mental retardation syndrome; N/A - Not available

ALOPECIA AREATA: TOTALIS AND UNIVERSALIS

Clinical presentation and etiopathogenesis

Alopecia areata (AA) (OMIM 104,000), including AT and AU, is an autoimmune-driven disorder resulting in nonscarring hair loss. A child with AT or AU can present with patchy hair loss of the scalp (AA) before acute or gradual progression to complete hair loss of the scalp (AT) or complete hair loss of the scalp and body (AU). However, in one study of 643 children with AA, 57.7% of children initially presented with either AT or AU, with 6 years being the average age of onset.[2] Associated skin findings with careful exam may include nail dystrophy and pitting (seen in 10%–20% of patients) and absence of nose or ear hair. Trichoscopic scalp findings may include point hairs, dystrophic hairs, and yellow dots.[3] Commonly associated comorbid conditions in children with AT/AU include atopic dermatitis (32.7%), asthma (20.7%), hay fever (20%), and allergies (14.2%).[2]

AA is the leading cause of complete scalp alopecia in children, and its etiology involves both genetic and epigenetic components.[4] Recent comprehensive genome-wide association studies have improved the understanding of genetic mechanisms causing AA, AT, and AU. Genetic factors include human leukocyte antigen-DQB1 haplotype, as well as pathogenic mutations in MHC Class I polypeptide-related sequence A, cytotoxic T-lymphocyte antigen-4, protein tyrosine phosphatase nonreceptor type 2, interleukin 1 receptor antagonist, and TNF receptor-associated factor 1/C5.[4] Additional associated genes with the development of AT/AU are summarized in Table 1.

Diagnosis and treatment

If a child presents with sudden-onset complete hair loss, high clinical suspicion for AA should be maintained. Supporting information from the patient's history includes family history of AA diagnoses or concomitant diseases such as atopic dermatitis, asthma, hay fever, allergies, urticaria, vitiligo, or psoriasis.[2] If the symptoms of hypothyroidism exist in the patient, a thyroid screen is prudent.

Empiric treatment involves topical or intralesional corticosteroids, with a positive response to therapy better supports the diagnosis of AA. Definitive diagnosis of AT/AU can be made with a scalp biopsy; however, most patients do not require one for diagnosis. Histologic appearance of AT/AU can vary depending on the stage of the condition. Acute phase is categorized by lymphocytic infiltrate surrounding the terminal hair bulb. Chronic phase AT/AU shows miniaturized follicles and a large proportion of catagen/telogen hairs with minimal to no peribulbar inflammation.[3]

Due to the remitting and relapsing course of AT/AU, the condition remains a therapeutic challenge. Topical or intralesional corticosteroids have only a modest response in most patients with complete hair loss. Additional potential therapies include phototherapy, topical sensitizers (i.e., diphenylcyclopropenone and anthralin), oral pulse or systemic steroids (i.e., prednisone), and methotrexate. An emerging therapeutic option is Janus Kinase inhibitors, with promising results in AT/AU clinical trials.[2]

HEREDITARY VITAMIN D-RESISTANT RICKETS, TYPE IIA

Clinical presentation and etiopathogenesis

Infants with HVDRR Type IIA (OMIM: 277,440) present with alopecia in 80% of cases; however, the pattern and age of onset are highly variable. Most commonly, the infant is born with a normal hair density but begins to shed rapidly with extensive alopecia by 3 months of age. The hair loss may involve scalp alone, or extend to involve total body alopecia.[5] Additional skin findings in HVDRR include cystic papules in areas including the scalp, face, and extremities.[6,7] Other findings include dental caries, growth retardation, hypotonia, skeletal abnormalities, and motor development delay.[6,7] Severe complications include seizures and pneumonia.[6] Although HVDRR presents with a wide range of musculoskeletal defects, alopecia can be an early indicator of the disease.

HVDRR is a rare, autosomal recessive (AR) form of rickets – a disease classically seen in children due to dietary Vitamin D deficiency. In all the forms of rickets, low Vitamin D leads to hypokalcemia. Within the first few months of life, resulting musculoskeletal findings include anterior protrusion of the sternum, rachitic rosary, frontal bossing, and leg bowing (as the infant begins walking).[6] HVDRR occurs due to pathogenic variants in the Vitamin D receptor (VDR) gene, located on the 12q12-q14 locus. So far, approximately 50 disease-causing VDR variants have been identified.[6] Although the pathogenesis and mechanism of alopecia in HVDRR are not fully understood, it is known that alopecia-inducing VDR mutations result in impaired anagen initiation.[5]

Diagnosis and treatment

Diagnosis of HVDRR is based on the family history and diagnostic criteria as well as laboratory findings. Among patients with HVDRR, those with alopecia are diagnosed earlier than those without alopecia.[8] Common laboratory abnormalities include hypocalcemia, hypophosphatemia, hyperparathyroidism, elevated alkaline phosphatase, and elevated calcitriol levels. Clinical signs of hypocalcemia can include convulsions and/or abnormal electrocardiogram findings such as a prolonged QT interval.[9] Although these findings can provide compelling clues for diagnosis, a scalp biopsy showing follicular remnants and cysts in the place of hair follicles may also support a HVDRR diagnosis. If physical examination, laboratory and biopsy findings do confirm the diagnosis, genetic testing for VDR mutations may be pursued.

The first-line treatment for HVDRR is oral calcitriol. If treatment with Vitamin D derivatives fails, additional options include intensive oral calcium supplementation and parenteral calcium infusions as last resort.[6] Interestingly, while vitamin supplementation may be effective for hypokalcemia and rickets, no treatment to date has been shown to effectively promote hair regrowth.

CONGENITAL ATRICHIA WITH PAPULAR LESIONS AND ALOPECIA UNIVERSALIS CONGENITA

Clinical presentation and etiopathogenesis

An infant with congenital APL (OMIM: 209,500) or AUC (OMIM: 203,655) may be born with a normal amount of scalp hair but quickly begins to lose hair in the first few weeks of life. In addition, eyelashes may be sparse or absent, and body hair fails to develop with age.[10] Both conditions have a similar course and are due to the mutations of the human hairless (HR) gene, located on chromosome 8p21.[11] A differentiating factor of APL from AUC is the presence of widespread follicular-based papules on the scalp, face, elbows, and upper or lower extremities in the first few years of life.[10]

APL is an AR condition commonly arising in individuals of consanguineous descent, notably in Pakistan, Iran, and Ireland.[12,13] The mutated gene, HR, functions as a necessary regulator of apoptosis during hair follicle regression (catagen).[14] Deleterious genetic variations within the HR gene affect hair follicle generation as well as lead to apoptosis of the hair follicle cells.[14] Prior to genetic characterization, all patients with APL present with similar findings with sporadic cases being frequently misdiagnosed as AU.[11]

Like APL, AUC is caused by the pathogenic variants in the HR gene; however, it does not present with skin papules. AUC may be inherited in autosomal dominant (AD), X-linked recessive (XLR), and AR pattern. The AD form presents with mild patches of scalp alopecia beginning in childhood or later.[15] The XLR form was reported in one Japanese family and resulted in total scalp alopecia.[16] The most common and severe form of AUC is AR, which results in complete body hair loss.[15]

Diagnosis and treatment

Because AUC and APL share a pleiotropic genotype, the presence or absence of papules can differentiate the two conditions. Diagnostic evaluation includes scalp biopsy and genetic testing. In APL, biopsy will demonstrate reduced or absent follicles and horn cysts.[17] Provided HVDDR also presents with keratin-filled cysts on histology, genetic testing is the gold standard for APL diagnosis confirmation.[7,17] Biopsy of a patient with AUC will also show atrophic or absent hair follicles but lack horn cysts.[7] Prognosis for hair regrowth in both conditions is poor, and no treatment options have yet been reported in the literature.

PURE HAIR AND NAIL ECTODERMAL DYSPLASIA

Clinical presentation and etiopathogenesis

PHNED (OMIM: 602,032) encompasses a group of rare conditions manifesting hair loss with varying severity, ranging from hypotrichosis of the scalp to complete body alopecia. In addition, infants present with nail defects involving all 20 nails. Nail findings include onychodystrophy, koilonychia, nail fragility, and/or nail discoloration.[18] These changes are typically evident at birth.[19] While PHNED is a member of the ectodermal dysplasia (ED) family of syndromes, children with PNHED characteristically lack ectodermal changes beyond the hair and nail abnormalities described, such as hypohidrosis, tooth changes, or dysmorphic facies. PHNED also lacks nonectodermal changes associated with ED such as skeletal anomalies, immunodeficiency, or developmental delay.[18]

Both AD and AR forms of PHNED have been reported. The AD form is associated with hypotrichosis; however, the gene has not been identified.[20] OMIM classifies AR PHNED into five subtypes: ED, types 4–7 and 9. Of these, types 4, 6, and 9 may result in complete alopecia. The genes identified for types 4 and 9 include Keratin 85 (KRT85) (chromosome 12q13.13) and Homeobox C13 (HOXC13) (chromosome 12q13.13–12q14.3), respectively.[19,21] KRT85 and HOXC13 play a role in keratin 2 formation, which is crucial in hair and nail production.[19] Type 6 ED, as reported in one Pakistani family, has been associated with complete scalp alopecia at birth and curly, sparse hair by age four.[22] The gene for type 6 has not been identified; however, the mutation is known to lie along chromosome 17p12–q21.2.[22] Given the rarity of PHNED, definitive phenotype-genotype correlations have yet to be established.[23]

Diagnosis and treatment

Dystrophic nails and complete scalp alopecia or hypotrichosis in children should raise concern for ED, with negative evaluation for sweating difference, tooth abnormalities, and intellectual disability pointing toward PHNED. In addition to frank alopecia and 20 nail dystrophy, broken hair shafts may be noted upon close examination and trichoscopy. Scalp biopsies show reduced hair follicles and disorganized hair shafts.[24] Although hair changes are common in ED, complete alopecia with nail dystrophy in the absence of additional ectodermal abnormalities is a strong indicator of PHNED. Currently, the treatment of PHNED is supportive care.

ALOPECIA WITH MENTAL RETARDATION

Clinical presentation and etiopathogenesis

In a child with suspected mild-to-severe intellectual disability, the presence of partial to complete alopecia may suggest a diagnosis of APMR.[25] APMR is a rare AR condition that has primarily been reported in a consanguineous families of Pakistani and Iranian descent.

It has been classified into three types, each corresponding to a distinct locus: APMR1 (3q26.33–q27.3), APMR2 (3q26.33–q26.31), and APMR3 (18q11.2–q12.2).[25,26,27] Each subtype of APMR has varying mental retardation: APMR1 (IQ: 25–54), APMR2 (IQ: 53–61), and APMR3 (IQ: 25–30). Moreover, APMR1 has partial to complete scalp alopecia, while APMR2 and APMR3 also have complete body alopecia. Given the rarity of APMR, the genotype-phenotype correlations have been somewhat tenuous. Although alopecia and intellectual disability are the main features of APMR, additional characteristics have been reported including epilepsy, growth retardation, microcephaly, and hypogonadism.[28,29]

Diagnosis and treatment

While genetic testing can be used to identify mutations, clinical presentation of intellectual disability and alopecia should alone raise concern for AMPR. The prognosis for hair regrowth is poor, as there are no treatment options noted in the literature.

DISCUSSION

In early onset diffuse alopecia in a child, genetic causes should be considered. In a majority of cases, a child presenting with total scalp alopecia will likely have AT/AU. However, when attempts at treatment fail and biopsy results are not consistent with AT/AU, it may be reasonable to expand the differential diagnosis. Aside from AT/AU, the most commonly described genetic conditions that cause early-life complete scalp alopecia include APL, AUC, HVDRR, APMR, and PHNED [Figure 1].

Figure 1.

Diagnostic flow chart for the workup of genetic complete scalp alopecia in an infant or child under the age of eight. *Given there are multiple ectodermal dysplasias, for differentiation consider genetic panel testing, eccrine function evaluation, trichoscopy, and scalp biopsy

To aid the clinician in the diagnosis, full body skin examination should always be a part of the workup. When a child presents with numerous milia-like papules and no other systemic symptoms, APL should be considered. If the child has papules with bone defects, neuromuscular delay, and hypocalcemia, clinicians should consider HVDRR. Although HVDRR is associated with the significant signs and symptoms of rickets, its full clinical spectrum may not fully manifest during the first few months of life.[30] Because systemic effects may have a delayed presentation and scalp biopsies may be identical, laboratory workup and genetic testing may ultimately differentiate APL and HVDRR.[9] This distinction is important given the necessity for vitamin supplementation in HVDRR.

When a child presents with alopecia but no skin papules, the differential diagnosis changes. If the patient also presents with nail dystrophy, the etiology points to AT/AU or PHNED. Given PHNED's rarity, it is most probable that the child will have a diagnosis of AT/AU. Genetic testing can confirm a diagnosis of PHNED, but scalp biopsy is the gold standard for AT/AU diagnosis.

In a young child with alopecia without nail or skin changes, scalp biopsy and genetic testing may aid in the diagnosis of AUC. Biopsy typically shows an absence of keratin-filled papules, and genetic testing demonstrates a pathogenic variant in HR. Given that HR mutations are found in both AUC and APL, these two diseases may lie along the same disease spectrum. Finally, evidence of intellectual disability with alopecia as the child grows, in the absence of other systemic symptoms or dermatologic findings, may indicate a diagnosis of AMPR.

Additional syndromes in which total scalp alopecia is an early childhood presenting symptom include growth retardation, alopecia, pseudoanodontia and optic atrophy, Ichthyosis follicularis, atrichia, and photophobia, Hutchinson-Gilford Progeria syndrome, and severe T-cell Immunodeficiency, and nail dystrophy. While these syndromes also present with complete alopecia, they are associated with severe craniofacial and/or cutaneous abnormalities, which aid the distinction from one another.

CONCLUSION

When presented with a case of total scalp alopecia in a child, it is important to consider the genetic etiologies as the part of a broad differential diagnosis. Early diagnosis assists clinicians in making appropriate treatment recommendations and monitoring clinical disease progression. Current literature identifies the most common genetic causes of complete scalp alopecia besides AT/AU to include HVDRR, APL, AUC, APMR, and PHNED. We propose an algorithm to help guide the clinicians in the diagnosis of genetic syndromes associated with complete scalp alopecia in early infancy and childhood.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.