Disorders of hair and nails

Trichorrhexis nodosa.

Trichorrhexis nodosa, the most common hair shaft anomaly, is a distinctive disorder manifested by increased fragility. ^, Grayish-white nodules may be seen on the hair ( Fig. 7.3 ), which under trichoscopy or light microscopy have the appearance of two interlocking brushes or brooms, the result of segmental longitudinal splitting of fibers without complete fracture. The disorder features dry, lusterless, short hair that is easily fractured.

Usually “acquired” in adolescents without other issues, trichorrhexis nodosa most commonly results from trauma to the hair. The injury may result from the use of hot combs, excessively hot hairdryers, hair straighteners, and other chemical treatments or the cumulative cuticular damage from vigorous combing and brushing, repeated salt-water bathing, prolonged sun exposure, and frequent shampooing. Cream rinses and protein conditioners are helpful. If hair-straightening procedures, vigorous grooming habits, and thermal and chemical trauma to the hair are discontinued, the acquired form of trichorrhexis nodosa generally improves within 2 to 4 years.

Less commonly trichorrhexis nodosa is genetic and manifests during infancy. Infants with the autosomal dominant form show normal hair at birth, but the hair that regrows within a few months is abnormal; the hair defect tends to improve with advancing age. Trichorrhexis nodosa may also be a manifestation of children with the late-onset form of argininosuccinic aciduria, a condition that results from lack of argininosuccinase. In this condition, the hair is usually normal at birth and first becomes fragile at 1 to 2 years of age with a dull, matted appearance, especially at the occipital area. The hair defects are associated with psychomotor retardation, cerebellar ataxia, and a marked increase of argininosuccinic acid in the blood, urine, and cerebrospinal fluid. ^, Dietary treatment of the metabolic abnormality leads to normalization of the appearance and integrity of the hair. Similar clinical manifestations are found in infants with citrullinemia, caused by a deficiency of argininosuccinic acid synthetase. Trichorrhexis nodosa is the most common hair shaft abnormality, but pili torti has been described and hair bulbs may be atrophic. Some patients show an eruption that resembles acrodermatitis enteropathica. Trichorrhexis nodosa has also been described in oculodentodigital dysplasia, ^, trichothiodystrophy (TTD), and trichohepatoenteric syndrome, characterized by facial dysmorphism, liver disease, immune defects, and severe diarrhea requiring intravenous nutrition.

Monilethrix.

Monilethrix (beaded hair) is an autosomal dominant disorder characterized by partial alopecia from breakage and variation in hair shaft thickness with small node-like deformities that produce a beaded appearance and internodal fragility. The nodal pattern can be seen by trichoscopy ( Fig. 7.4 ) but can be subtle. ^, In individuals with this disorder, normal neonatal lanugo hairs are shed during the first few weeks of life. The regrown hair, which generally appears at about the second month of life, is dry, lusterless, and brittle and fails to grow to any appreciable length because of breakage ( Fig. 7.5 , A ). In severe cases, the infant may remain bald or the scalp hair may be sparse, easily fractured, and stubble-like with follicular prominence from keratosis. Although generally a disorder of scalp hair, body hairs may also be affected. The clinical findings are limited to the occiput and nape in more limited cases ( Fig. 7.5 , B ). Occasionally this disorder is not apparent during infancy but becomes apparent later in childhood or during adult life. Follicular keratosis is associated in some pedigrees and may affect the face, scalp, and extremities. Some patients show koilonychia. Spontaneous improvement or remission may occur at puberty or during pregnancy, suggesting a hormonal influence, but the condition may persist unchanged throughout adulthood. Administration of oral retinoids, topical minoxidil, and low-dose oral minoxidil have been reported to improve the alopecia.

Monilethrix most commonly is autosomal dominant and results from mutations in hair (or trichocyte) keratins. These hair keratins have a high cysteine content, making them “hard” keratins with a high degree of crosslinking. Of the 26 known hair follicle–specific keratins, three have been associated with monilethrix and all are type II keratins. Mutations in KRT81 and KRT86 are most common. Mutations in KRT83 also lead to monilethrix, ^, but homozygous deletion variants in KRT83 result in generalized ichthyosis with palmoplantar keratoderma and no hair defects. Because keratins provide structural integrity to hair, abnormalities in these keratins lead to hair fragility, with breakage occurring at the internodal sites. Mutations in hair keratins have also been linked to pure hair and nail ectodermal dysplasia (PHNED) ( KRT85 ), woolly hair with hypotrichosis ( KRT71 and KRT74 ), and pseudofolliculitis barbae ( KRT75 ). The majority of the hair keratins remain unlinked to human phenotypes but may impart variants in hair strength, texture, or curliness.

Autosomal recessive monilethrix has been linked to mutations in DSG4 , which encodes desmoglein 4, a transmembranous cell-adhesion molecule of the cadherin family that is predominantly expressed in the hair cortex and upper cuticle. Desmoglein 4 is thought to integrate keratin filaments into desmosomes. Desmoglein 4 mutations may also manifest as autosomal recessive hypotrichosis, which resembles monilethrix but lacks the characteristic beaded appearance of the hair shaft under light microscopy.

Pseudomonilethrix.

Pseudomonilethrix was originally described as an autosomal dominant developmental defect of fragile hair with irregularly shaped nodes. ^, In fact, the hair changes are artifactual and related to overlapping hairs under the pressure of an overlying glass slide. Pseudomonilethrix is seen more commonly when fine hairs are handled by forceps.

Trichorrhexis invaginata.

Trichorrhexis invaginata (bamboo hair) is characterized clinically by dry, lusterless, easily fractured, sparse, and short hair. Under light microscopy, the hairs show a peculiar intussusception or telescope-like invagination along the hair shaft, which microscopically resembles the ball-and-cup joints of bamboo. ^, Variations in trichorrhexis invaginata occur, most commonly “golf-tee hair,” presenting the expanded proximal end of an invaginate node, which is easily seen by trichoscopy. The hair defect in trichorrhexis invaginata is thought to be abnormal keratinization of the hair shaft, which results in softening of the hair cortex and promotes intussusception of the distal portion of the hair shaft into the softer proximal portion.

Although trichorrhexis invaginata may occur as an isolated finding, this hair shaft abnormality is characteristic of Netherton syndrome (see Fig. 7.6 ), an autosomal recessive genodermatosis that has been linked to mutations in SPINK5 (see Chapter 5 ). Neonates with this disorder characteristically show generalized exfoliative erythroderma and failure to thrive, often associated with hypernatremic dehydration, recurrent infections, and sepsis. Severely affected neonates may show extremely sparse and even absent hair, making the diagnosis based on hair shaft examination difficult. However, the eyebrows are almost always short and broken ( Fig. 7.6 , A and 5.35 ); eyebrow hairs should be examined in cases in which the abnormality cannot be demonstrated from scalp hair, and trichoscopy (dermoscopy) can be helpful. ^,

Beyond infancy, many affected individuals show the characteristic skin finding of ichthyosis linearis circumflexa, with walls of scale surrounding red patches, in addition to their dry, lusterless hair that breaks easily (see Fig. 7.6 , B and Fig. 5.34 A ). Atopic conditions usually accompany the ichthyosis. Although spontaneous remission of the hair defect has been described (generally between 6 and 15 years of age), the vast majority show persistence.

Pili torti.

Pili torti hairs show three or four regularly spaced twists that occur at irregular intervals along the hair shaft. ^, The hair shaft appears flattened at the site of the twist, which is almost always through 180 degrees. The dry, fragile hair is often lighter in color than expected and shimmers in reflected light with a “spangled” appearance because of the hair twisting. The hair tends to be short, especially in areas subject to trauma, and may extend out from the scalp. Pili torti must be distinguished from twisted hair, which has been described in association with anorexia nervosa.

Pili torti may occur as an isolated phenomenon with onset at birth or early infancy. This genetic disorder shows both autosomal dominant and autosomal recessive inheritance patterns. The appearance of the hair in patients with pili torti may become more normal with time, although twisted hairs can still be found in the adult scalp; those who still manifest the disorder at puberty, however, are unlikely to show significant improvement with age. A late-onset autosomal dominant form has also been described, in which brittle hair and patchy alopecia develop after puberty. Mental retardation has been noted in some pedigrees. Pili torti has been associated with several mitochondrial disorders (see Pili Torti section).

Menkes syndrome (trichopoliodystrophy) is an X-linked recessive neurodegenerative disorder that affects male infants. Classic Menkes syndrome affects 90% to 95% of patients, with a less common mild form associated with long survival and occipital horn syndrome (previously called X-linked cutis laxa or Ehlers–Danlos syndrome type IX) showing largely connective tissue manifestations. Carrier females may exhibit pili torti. Classical Menkes syndrome is characterized by coarse facies; pili torti; temperature instability; seizures; psychomotor retardation; arterial intimal changes; soft, doughy skin that may resemble localized areas of cutis laxa ; joint laxity; low or absent plasma copper and ceruloplasmin levels; growth failure; increased susceptibility to infection; and death, generally by age 3 or 4 years. ^, Clinical features often include premature birth, hypothermia, and relatively normal development until 2 to 6 months of age, when drowsiness and lethargy are noted, intractable seizures begin, and growth and development cease. Rarely neonates demonstrate erythroderma as an early sign.

Usually the hair is fine, dull, sparse, and poorly pigmented in infancy; it stands on end and looks and feels like steel wool ( Fig. 7.7 ). Additional features include tortuosity of cerebral and other medium-sized arteries; osteoporosis; frequent subdural hematomas; widening of the metaphyses with spurring; and frequent fractures, at times simulating the radiologic findings characteristic of patients with battered child syndrome. Although pili torti is generally a prominent feature of this disorder, other less commonly reported hair abnormalities include monilethrix and trichorrhexis nodosa.

Menkes syndrome results from mutations in ATP7A, which encodes a copper-transporting adenosine triphosphatase (ATPase) that incorporates copper into copper-dependent enzymes and maintains copper levels by removing excessive copper from the cytosol. The combination of clinical features, bone abnormalities, and low plasma copper and ceruloplasmin levels establishes the correct diagnosis. Parenteral administration of copper histidine occasionally prevents neurologic degeneration and pigmentation if initiated in the neonatal or infantile period but often is ineffective.

Crandall syndrome, an X-linked recessive disorder, consists of pili torti with alopecia, sensorineural deafness, and hypopituitarism. Björnstad syndrome is characterized by sensorineural deafness, pili torti, and occasionally mental retardation. The syndrome is autosomal recessive, but families with an autosomal dominant pattern have been described. The recessive form has more recently been linked to mutations in BCS1L, which encodes an ATPase needed to assemble complex III in the mitochondria. More severe defects in BCS1L markedly increase reactive oxygen species and are lethal to neonatal infants with multisystemic involvement (complex II deficiency and growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death [GRACILE] syndrome).

Bazex–Dupré–Christol and Rombo syndromes are X-linked dominant traits characterized by congenital hypotrichosis with pili torti, numerous facial milia, trichoepitheliomas, vellus hair cysts, and an increased risk of the early development of basal cell carcinomas. ^, Distinguishing features are follicular atrophoderma, hypohidrosis, comedones and facial and neck pigmentation in Bazex–Dupré–Christol syndrome, and atrophoderma vermiculatum and photosensitivity in Rombo syndrome. Females often do not show the hypotrichosis, with normal and pili torti hairs intermingled.

Hypotrichosis with juvenile macular dystrophy (HJMD) is characterized by the development of sparse, short hair from birth or in the first months of life. Fusiform beading and pili torti may be seen by microscopy. Macular degeneration first develops in the first or second decade, leading to blindness by early adulthood. Patients suspected of having HJMD should have annual ophthalmologic evaluations, because early retinal pigmentation and atrophy precede the decrease in visual acuity. The disorder is autosomal recessive and caused by mutations in CDH3, which encodes P-cadherin. ^, CDH3 mutations also cause ectodermal dysplasia, ectrodactyly, and macular dystrophy ( Table 7.1 ).

Individuals with mitochondrial enzyme abnormalities have shown a wide variety of abnormalities, predominantly failure to thrive and neuromuscular changes; however, skin or hair abnormalities have been described in 10% of affected children. Hair abnormalities range from alopecia to dry, thick, brittle hair to hypertrichosis, especially on the back. Syndromic disorders with hair abnormalities may also affect mitochondrial function (e.g., Björnstad syndrome and cartilage–hair hypoplasia). Light-microscopy examination of affected hair has shown a variety of hair shaft defects associated with increased fragility, including pili torti, TTD, trichorrhexis nodosa, and diffuse longitudinal grooving with flattened hair shafts. ^, Patchy erythematous lesions have been described, and many of the patients with skin manifestations have shown mottled pigmentation.

Pili bifurcati.

Pili bifurcati is an uncommon anomaly of hair growth characterized by intermittent bifurcation of the hair shaft in which affected hairs divide into two separate shafts that subsequently become rejoined along the hair shaft. ^, This bifurcation is repeated at intervals, and the anomaly appears to be transitory, with only a small percentage of hairs exhibiting the bifurcation. This disorder should not be confused with pili multigemini, a disorder in which multiple hairs project from a single hair follicle.

Trichothiodystrophy.

TTD is a heterogeneous group of autosomal recessive disorders in which patients have dry, brittle, cysteine-deficient hair as an isolated finding or in association with often-multisystemic disease. To date, four genes have been linked to autosomal recessive TTD: ERCC2 (XPD) , ERCC3 (XPB) , p8 or GTF2H5 (TTDA) , and C7Orf11/ MPLKIP (TTDN1) . The function of TTDN1 is not well understood, but it likely regulates cell cycling and transcription efficiency. The other three genes encode subunits of transcription/repair factor IIH (TFIIH), a multiprotein complex involved in transcription and nucleotide excision repair. ^, A recently described form of autosomal recessive TTD results from mutations in GTF2E2, which encodes a subunit of the basal transcription factor II E (TFIIEβ) and is associated with proficient nucleotide excision repair.

Light microscopy of TTD hairs shows a wavy, irregular outline and a flattened shaft that twists like a folded ribbon. Two types of fracture may be seen: trichoschisis (clean transverse fracture) or an atypical trichorrhexis nodosa with only slight splaying of the cortical cells. Trichoscopy using polarized light or polarizing microscopy shows the characteristic alternating light and dark bands, the “tiger-tail” appearance. Although the severity of hair shaft defects is inversely proportional to the hair sulfur content, there is no association between the extent of systemic disease and percentage of abnormal hairs. Sparse hair is often associated with the shaft defect. Some patients have described cyclic hair loss with fever, which may reflect a mutation leading to thermosensitive XPD .

A review of 112 published cases of TTD described the abnormalities beyond hair defects. Ichthyosis has been noted in 65% and clinical evidence of photosensitivity in 24% of these patients. The ichthyosis may resemble autosomal recessive congenital ichthyosis (ARCI) or ichthyosis vulgaris (see Chapter 5 ), and some patients show marked depletion of the granular layer in skin biopsy sections. Of the patients who have TTD with ichthyosis, 37% show a collodion phenotype at birth. Patients may also show xerosis, palmoplantar keratoderma, atopic dermatitis, and/or follicular keratosis. Nail abnormalities have been described in 63% of patients overall, especially dystrophy with thickening or yellow discoloration.

Among the most common noncutaneous features are developmental delay/intellectual impairment (86%), short stature and low weight (73%), and ocular abnormalities (51%, especially cataracts). Facial dysmorphism is seen in 66% of patients, especially microcephaly, large or protruding ears, and micrognathia. An outgoing personality is a characteristic feature. Bone abnormalities are seen radiographically in 38%, particularly osteosclerosis and delayed bone age. Gonadal abnormalities were noted in 14% overall, most commonly hypogonadism and cryptorchidism. Recurrent infections have been noted in 46%, particularly involving the respiratory and gastrointestinal tracts and the inner ear, but were uncommonly associated with immunodeficiency or neutropenia. ^, Overall, mortality in the first decade of life is increased 20-fold. Not only is there the increased risk of infection, but children with TTD are at high risk for poor outcomes after routine procedures. Complications during pregnancy are noted in 26% of patients, most commonly intrauterine growth retardation, but also preterm delivery; preeclampsia; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; and prematurity. ^, The newly described form (GTF2E2) is a nonphotosensitive form and is characterized by ichthyosis, failure to thrive, and delayed motor and cognitive development. Unlike xeroderma pigmentosum, TTD is not prone to cancer, although squamous cell carcinoma has been described. ^,

Subgroups of TTD have been classified based on clinical characteristics (brittle hair, intellectual impairment, decreased fertility, and short stature [BIDS]; ichthyosis, brittle hair, infertility, developmental delay, short stature [IBIDS]/Tay syndrome; photosensitivity, ichthyosis, brittle hair, infertility, developmental delay, short stature [PIBIDS]). However, a new classification has been proposed that divides patients based on their mutations as group I (mutations in genes encoding subunits of TFIIH: XPD/ERCC2, XPB/ERCC3, TTDA, or p8/GTF2H5 ), II ( TTDN1/MPLKIP and GTF2E2 ), and III (no known molecular basis). Group I includes patients with photosensitivity (either clinical or in vitro ) and is the most common subtype. Most individuals in group II are not photosensitive and show an increased risk of developmental delay, delayed bone age, seizures, and autistic behavior. Currently unclassified but nonphotosensitive patients (such as those with Pollitt and Sabinas syndromes, which have been linked to gene defects) are in group III. Using this classification, ichthyosis and the collodion-baby phenotype are most highly correlated with group I, whereas hypogonadism has been found more in groups II and III.

An X-linked form of nonphotosensitive TTD has been described, characterized by the typical sparse, brittle hair; severe intellectual impairment with microcephaly; and short stature, but also facial dysmorphism and an aged appearance, hypogammaglobulinemia, seizures, endocrine abnormalities, and brain malformations. Ichthyosis and photosensitivity are not features. The disorder results from mutations in RNF113A, which encodes a protein of unknown function.

Marie unna hypotrichosis.

Marie Unna hypotrichosis is an autosomal dominant disorder manifested by almost complete congenital absence of scalp hair, eyebrows, and eyelashes. The hair regrows to normal density but is coarse, flattened, and twisted. Beginning at puberty the hair becomes progressively sparser, particularly on the vertex and scalp margins, resulting in a high frontal ( Fig. 7.8 ) and nuchal hairline. By adulthood, only a sparse fringe of hair at the scalp margin may remain, and eyelashes, eyebrows, and body hair, including secondary-sexual hair, tend to be sparse. Scattered follicular horny plugs may be associated but no scarring. Trichoscopy/light microscopy of the shaft shows variations in shaft diameter and twisting or bending at odd angles. Other ectodermal structures are unaffected, except that 50% of affected individuals show exceptionally widely spaced upper incisor teeth. Mutations that cause Marie Unna hypotrichosis affect U2HR, an open-reading frame upstream of the hairless gene that inhibits hairless expression; as a result, hairless expression and Wnt signaling are increased. ^,

Pili annulati.

Pili annulati (ringed hair) is an autosomal dominant condition with onset shortly after birth. The hair looks shiny with attractive highlights but has alternating bright and dark bands on close inspection. The bright areas are the result of light scattering from clusters of air-filled cavities within the cortex that appear as dark areas under light microscopy, especially in more proximal hair regions. Pili annulati may increase the risk of developing AA and has been reported to markedly improve or clear after the occurrence of alopecia totalis. The gene mutated in pili annulati has been linked to chromosome 12q24.33, but no mutations in candidate genes have been found.

Pseudopili annulati is an unusual variant of normal hair in which bright bands are seen at intervals along the hair shaft. Secondary to periodic twisting or curling of the hair shaft, this banding is conspicuous only in blond hairs and represents an attractive optical effect caused by reflection and refraction of light by flattened and twisted hair surfaces.

Acquired progressive kinking of the hair.

Acquired progressive kinking of the hair is a rare disorder of scalp hair, with onset in adolescence or in young adulthood. The condition is characterized by a rapid onset of extreme curliness of the hair (mainly on the frontoparietal region of the scalp and vertex), often in association with an increased coarse texture, diminished luster, and striking unruliness. The disorder is more common in males than in females. Hair may become darker or remain unaltered in color, and the rate of growth may be decreased or unchanged. Examination of abnormal hairs by light microscopy reveals alterations in hair shaft diameter and partial twisting of the hair on its longitudinal axis.

Although the etiology of this disorder is unknown, it may follow treatment with systemic retinoids, including isotretinoin. The localization of hair kinking, family history of androgenetic alopecia (AGA), pathologic features of the affected scalp, and tendency to evolve into AGA suggest acquired kinking as a harbinger of AGA. No therapy is effective, and application of topical minoxidil has not affected the progressive thinning of hair in the areas of kinking. Spontaneous reversion to normal hair has been reported. Coarse hair, but not woolly hair, is also a feature of Hajdu–Cheney syndrome, resulting from mutations in NOTCH2. Other features include craniofacial abnormalities, short stature, acroosteolysis with broad nails and digits, synophrys, coarse skin, and premature tooth loss with periodontitis.

Uncombable hair syndrome.

The uncombable hair syndrome (pili trianguli canaliculi, spun-glass hair syndrome) is a unique hair disorder characterized by very pale, silvery, blond, or straw-colored hair. The hair is dry, frizzy, and unruly, and it does not lie flat on the scalp, thus making combing impossible ( Fig. 7.10 ). ^, The syndrome is autosomal recessive and results from mutations in one of three genes: PADI3 (encoding peptidylarginine deiminase 3), TGM3 (encoding transglutaminase 3), or TCHH (encoding trichohyalin ). PADI and TGM3 are enzymes responsible for posttranslational modifications in trichohyalin, a hair shaft protein.

The onset is usually during infancy or early childhood, and eyebrows, lashes, and body hair are normal. Affected children may have minor nail abnormalities, and some show both uncombable hair and loose anagen hair (see Loose Anagen Syndrome section). However, more significant nail abnormalities or other features beyond the hair issue should prompt a search for a second disorder; one child with uncombable hair and congenital anonychia was found to have homozygous mutations in both PADI3 and RSPO4, encoding R-spondin 4 (see nails). The characteristic structural defect of uncombable hair—the presence of canalicular depressions along the hair shaft—can be demonstrated by scanning electron microscopy or by routine microscopy of the hair in cross-section. Cross-sectional microscopy shows a variety of shapes, including triangular, quadrangular, and reniform. The longitudinal grooving and abnormal shape in cross-section, however, are not specific for uncombable hair syndrome and have been described in several other syndromes, among them Marie Unna hypotrichosis, the ectodermal dysplasias with clefting, hypohidrotic ectodermal dysplasia (HED), oral-facial-digital syndrome type I (OFD1), and progeria. The clinical appearance of the spun-glass hair requires a sizable proportion of abnormal hairs, and at least 50% of hairs are abnormal by scanning electron microscopy. The hair tends to become progressively more manageable by adolescence, and some patients have responded to biotin administration.

Uncombable hair syndrome must be distinguished from extremely unruly hair, which is seen in 2% of individuals. Extremely unruly hair that tends to stand up from the area of the posterior parietal whorl toward the frontal hairline may be associated with microcephaly and is a potential indicator of abnormal brain growth and morphogenesis, similar to upsweep of anterior scalp hair and aberrant parietal whorl position.

Congenital triangular alopecia.

Congenital triangular alopecia is characterized by an area of alopecia that, although sometimes notable at birth in babies with abundant scalp hair, is usually detected at 2 or 3 years of age ( Fig. 7.12 ). It is often earlier in boys than girls because of the shorter hair. An initial appearance during adulthood has been described. The area is triangular and overlies the frontotemporal suture, with the base of the triangle directed forward. The triangular patch may extend to the hairline, but often a fringe of hair may separate it from the forehead. Generally measuring 3 to 5 cm from base to apex, the area may be completely bald or partially covered by vellus hairs and remains unchanged throughout life. The differential diagnosis includes AA, trichotillomania, and traction alopecia. Dermoscopy of the affected area shows normal follicular openings with vellus hairs, whereas dermoscopy of AA shows dystrophic and exclamation-point hairs. Although unilateral in 80% to 90% of affected individuals, it may be bilaterally symmetric, and on rare occasions, similar triangular patches may be noted on the temporoparietal area, occipital scalp, or nape.

The condition is almost always sporadic, although the association with developmental delay and seizures has been described in a mother and daughter. Congenital triangular alopecia has been described in a patient each with phakomatosis pigmentovascularis, Down syndrome, and Dandy–Walker malformation. Hair transplants have been used to repopulate the area of triangular alopecia. Bilateral congenital localized patches of alopecia of the parietal area that resemble the alopecia of congenital triangular alopecia have been seen in patients with Gomez–Lopez–Hernandez syndrome (cerebellotrigeminal–dermal dysplasia). Although the alopecia classically affects the parietal area, other sites have been reported to show symmetric alopecia. Other features are skull defects (craniosynostosis with brachycephaly, midfacial hypoplasia), neurologic abnormalities, short stature, hypertelorism, and corneal opacities.