alopecia

Encephalocraniocutaneous Lipomatosis

Clinical Characteristics
Ocular Features: 

Ocular choristomas of the periocular tissue such as epibulbar dermoids or lipodermoids are seen in 80% of individuals.  Some degree of microphthalmia, a 'hypertrophic' conjunctiva, and sclerocornea have been reported.  The pupils are small and iris hypoplasia with anterior chamber anomalies has been described.  The macular reflex can be absent and colobomas of the eyelids (and rarely uveal tract) have been seen.

Systemic Features: 

Preauricular skin tags may be present.   Fatty tissue nevi associated with alopecia as well as frontotemporal or zygomatic subcutaneous fatty lipomas, and focal dermal hypoplasia are seen externally in many patients.   Coarctation and/or hypoplasia of the thoracic aorta along with aortic valve anomalies are sometimes present.

Intracranial and intraspinal lipomas are present in over 60% of individuals.  Arachnoid cysts with ventricular enlargement, and leptomeningeal angiomatosis are frequently present.  Jawbone cysts and tumors are common. The skull and heart may also have lipomas.  Seizures and some intellectual disability have been diagnosed in many affected individuals but a third or more have normal intellect.  The affected cortex may calcify later in life.

Genetics

ECCL is considered to result from postzygotic activating mutations in the FGFR1 gene (8p11.23) resulting in a mosaic distribution.  This may help explain the highly variable and widespread distribution of skin and CNS lesions.  A 5-year-old female with an affected father and paternal grandmother have been reported suggesting autosomal dominant inheritance.

Mutations in the same gene have been found in Pfeiffer syndrome (101600).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the overall condition but selective removal of tumors with cosmetic and pressure consequences should be considered.

References
Article Title: 

Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis

Bennett JT, Tan TY, Alcantara D, Tetrault M, Timms AE, Jensen D, Collins S, Nowaczyk MJ, Lindhurst MJ, Christensen KM, Braddock SR, Brandling-Bennett H, Hennekam RC, Chung B, Lehman A, Su J, Ng S, Amor DJ; University of Washington Center for Mendelian Genomics; Care4Rare Canada Consortium, Majewski J, Biesecker LG, Boycott KM, Dobyns WB, O'Driscoll M, Moog U, McDonell LM. Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis. Am J Hum Genet. 2016 Mar 3;98(3):579-87.

PubMed ID: 
26942290

Mandibulofacial Dysostosis with Alopecia

Clinical Characteristics
Ocular Features: 

The extensive dysplasia of the facial bones involves those of the orbital rims and zygomatic arches.  The orbital rims can be malformed and there is often a broad depression at the inferolateral region of the eyes.  Hypoplasia or even aplasia of the eyelids maybe present and some individuals have colobomas of the lower eyelids.  The lacrimal punctae may be temporally displaced.  The eyebrows and eyelashes are often sparse as part of the generalized alopecia.

Systemic Features: 

This is a disorder of craniofacial development resulting in extensive malformations of facial bones and skin.  Different rates of development among these structures leads to facial asymmetry in many patients. Maxillary, zygomatic arch, and mandibular bones are dysplastic resulting in micrognathia and a flat midface.   The temporomandibular joints are absent and the external ear canals are often incompletely formed.  Conductive hearing loss is common with hypoplastic ossicular chains while the pinnae are low-set, crumpled and abnormally cupped.  There may be preauricular tags or pits present.  Tooth eruption is often delayed and there may be agenesis of many permanent teeth.  The maxillary sinuses may be absent.  Cleft palate is often present.

Genetics

Heterozygous mutations in the EDNRA gene (4q31) are responsible for this condition.  No familial cases have been reported and it can be assumed that the mutations arise de novo. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the overall condition but individual anomalies such as the colobomas, dental deformities and cleft palate may be surgically repaired.  Upper airway obstruction may require tracheostomy in infants.

References
Article Title: 

Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia

Gordon CT, Weaver KN, Zechi-Ceide RM, Madsen EC, Tavares AL, Oufadem M, Kurihara Y, Adameyko I, Picard A, Breton S, Pierrot S, Biosse-Duplan M, Voisin N, Masson C, Bole-Feysot C, Nitschke P, Delrue MA, Lacombe D, Guion-Almeida ML, Moura PP, Garib DG, Munnich A, Ernfors P, Hufnagel RB, Hopkin RJ, Kurihara H, Saal HM, Weaver DD, Katsanis N, Lyonnet S, Golzio C, Clouthier DE, Amiel J. Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia. Am J Hum Genet. 2015 Apr 2;96(4):519-31.

PubMed ID: 
25772936

Hypoparathyroidism, Familial Isolated

Clinical Characteristics
Ocular Features: 

Lens opacities may be present.

Systemic Features: 

The major signs and symptoms result from hypocalcemia. Neuromuscular irritability and various paresthesias may be present.  Some patients have  laryngeal spasm and latent tetany with grand mal seizures.  Alopecia, abnormal dentition and coarse brittle hair may be present.  Cognitive deficits and personality disorders are often a feature.  Brain imaging may show calcification of the basal ganglia.  Serum calcium levels are usually low while phosphorus levels are elevated.   Vitamin D precursor levels are usually low or low normal.

Genetics

Familial hypoparathyroidism may be due to mutations in the PTH gene (11p15.3) (either autosomal dominant or recessive inheritance) or in the GCMB gene (6p24.2) (autosomal dominant inheritance pattern).

There is also an X-linked form of hypoparathyroidism (307700) in which parathryroid tissue may be congenitally absent.

A family has been reported in which hypoparathryroidism was associated with lymphedema (247410) and progressive renal failure.  Ptosis, telecanthus, hypertrichosis, restrictive lung disease, and mitral valve prolapse may also be part of the disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Normalization of calcium and phosphorus levels is a priority and this may result in some clearing of the lens opacities.  Cataract surgery may be indicated in selected individuals.

References
Article Title: 

GAPO Syndrome

Clinical Characteristics
Ocular Features: 

Progressive optic atrophy is considered part of this syndrome but it is not a consistent feature.  One patient with the suspected diagnosis had papilledema while other individuals may have congenital glaucoma, buphthalmos, band keratopathy, and keratoconus.  White eyelashes have been described.  Myelinated nerve retinal nerve fibers may be prominent.

Systemic Features: 

This is a rare congenital disorder with so far incomplete phenotypic delineation. The diagnosis can be made soon after birth from the general facial and body morphology.  The dysmorphism is secondary to marked bone growth retardation and metaphyseal dysplasia, resulting in a flat midface, frontal bossing, micrognathism, chest deformities, and vertebral anomalies. Psychomotor retardation is common but the extent of cognitive deficits is unknown.  The permanent teeth may begin to develop but fail to erupt (pseudoanodontia). Even primary dentition is often abnormal.  Alopecia is a feature although some individuals do have sparse body hair, at least for a period of time.  Anomalous blood vessels such as dilated scalp veins are sometimes evident.   Hypogonadism has been reported in both sexes.  Individuals are subject to recurrent ear and respiratory infections. 

Genetics

GAPO occurs in both sexes.  Homozygous mutations in the ANTXR1 gene (2p13.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is directed at individual problems.  Prompt treatment of respiratory infections is important.

References
Article Title: 

Mutations in ANTXR1 cause GAPO syndrome

Stranecky V, Hoischen A, Hartmannova H, Zaki MS, Chaudhary A, Zudaire E, Noskova L, Baresova V, Pristoupilova A, Hodanova K, Sovova J, Hulkova H, Piherova L, Hehir-Kwa JY, de Silva D, Senanayake MP, Farrag S, Zeman J, Martasek P, Baxova A, Afifi HH, St Croix B, Brunner HG, Temtamy S, Kmoch S. Mutations in ANTXR1 cause GAPO syndrome. Am J Hum Genet. 2013 May 2;92(5):792-9.

PubMed ID: 
23602711

Ophthalmic findings in GAPO syndrome

Ilker SS, Ozturk F, Kurt E, Temel M, Gul D, Sayli BS. Ophthalmic findings in GAPO syndrome. Jpn J Ophthalmol. 1999 Jan-Feb;43(1):48-52.

PubMed ID: 
10197743

IFAP (BRESHECK) Syndrome

Clinical Characteristics
Ocular Features: 

The eyelashes and eyebrow hair is sparse or completely absent.  Keratitis with secondary photophobia is often seen during infancy and progresses to corneal vascularization and scarring, sometimes resembling trachomatous disease.  Cataracts do not seem to be part of this syndrome unlike some other genodermatoses.

Systemic Features: 

Dry, scaly skin and alopecia are usually evident at birth.  There is marked absence of hair throughout the body.  The skin is generally ichthyotic and erythematous, with continuous lamellar desquamation of surface skin.  Generalized follicular hyperkeratosis is present on the scalp, dorsal surface of the limbs and on the abdomen.  Most patients are completely bald.

In some patients the skin, hair and corneal disease is accompanied by severe internal anomalies such as kidney dysplasia, brain anomalies and mental retardation, Hirschsprung disease, cleft palate, external ear malformations, cryptorchidism, and skeletal deformities, a combination of signs that some have called BRESEK/BRESHECK syndrome.  Depending upon how extensive the organ involvement, the prognosis is usually guarded and patients may not live beyond early childhood. 

It is uncertain if IFAP refers to a single disorder or if two disorders are involved (see Genetics).

Genetics

This is generally considered to be an X-linked recessive disorder most likely due to mutations in MBTPS2, at least in patients considered to have the BRESHECK condition.  Female carrier may have some similar skin and hair signs albeit to a lesser degree than males.

Since the amount of MBTPS2 activity has been shown to vary with different mutations, it is possible that all cases of IFAP with or without the added BRESHECK findings are part of the clinical spectrum of a single disorder (variable expressivity).  

Other genodermatoses with severe keratitis are KID syndrome (148210) and Hereditary Mucoepithelial Dysplasia (158310).

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

MBTPS2 mutation causes BRESEK/BRESHECK syndrome

Naiki M, Mizuno S, Yamada K, Yamada Y, Kimura R, Oshiro M, Okamoto N, Makita Y, Seishima M, Wakamatsu N. MBTPS2 mutation causes BRESEK/BRESHECK syndrome. Am J Med Genet A. 2012 Jan;158A(1):97-102.

PubMed ID: 
22105905

IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response

Oeffner F, Fischer G, Happle R, Konig A, Betz RC, Bornholdt D, Neidel U, Boente Mdel C, Redler S, Romero-Gomez J, Salhi A, Vera-Casano A, Weirich C, Grzeschik KH. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Am J Hum Genet. 2009 Apr;84(4):459-67.

PubMed ID: 
19361614

Hereditary Mucoepithelial Dysplasia

Clinical Characteristics
Ocular Features: 

Impaired epithelial cohesion is the fundamental defect in this disorder.  Photophobia may be present in infants and this is soon evident as secondary to keratitis with eventual formation of a pannus and corneal neovascularization.  Vision is impaired early and as the disease progresses, many patients by early adulthood are severely impaired.  Cataracts are present in the majority of individuals, often present as early as the second decade of life.  Eyelashes and eyebrows may be sparse.  Nystagmus has been reported in some patients.

Systemic Features: 

This is a panepithelial disease of impaired cohesion due, at least in part, to a reduced number of desmosomes and defective gap junctions.  Oral, nasal, vaginal, cervical, perineal, urethral, and bladder mucosa, in addition to external ocular surfaces, are involved.  With exception of the ocular involvement, the lesions are usually not painful, but may be during acute flare-ups.  Demarcated erythematous patches are often seen in the oral mucosa.  Non-scarring alopecia, keratosis pilaris, and perineal intertrigo are usually present.  Histological examination of oral mucosa and skin shows dyskeratotic features, decreased number of desmosomes, and intracytoplasmic vacuoles.

Genetics

Pedigrees suggest autosomal dominant inheritance but few families have been reported.  The location of the responsible mutation, if any, has not been found. 

Somewhat similar genodermatoses are KID syndrome (148210), an autosomal dominant disorder with neurosensory hearing loss and sometimes mental and physical delays secondary to mutations in GJB2, and IFAP (308205), an X-linked condition with mental and physical delays and severe organ deformities.  Cataracts are not features of KID or IFAP syndromes.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been found.

References
Article Title: 

Ablepharon-Macrostomia Syndrome

Clinical Characteristics
Ocular Features: 

The clinical features of this syndrome remain to be fully delineated.  Important ocular anomalies include malformations and sometimes absence of the upper and lower eyelids.  The eyelashes and eyebrows may be sparse or even missing.  The lid fissures, if present, may be shortened.  Deformities of the eyelids can lead to corneal exposure and secondary vision loss. 

Systemic Features: 

Other facial malformations include macrostomia which may be secondary to aberrant lip fusion.  Micrognathia has been described.  The external ears are often rudimentary, sometimes described as rosebuds.  The nasal bridge is low and the nostrils anteverted.  The zygomatic arches may be absent.  The nipples are often missing as well.  Scalp hair is sparse or even absent while the skin is dry, coarse, and often has redundant folds (cutis laxa).  Mild skin syndactyly, camptodactyly, finger contractures, and shortening of metacarpals have been noted.  The genitalia are often ambiguous and some patients have had ventral hernias.  Hearing loss can be a feature.  Growth retardation has been seen but developmental delays if present are mild.  Intelligence can be normal. 

Genetics

The majority of sibships suggest autosomal recessive inheritance although autosomal dominant inheritance has been proposed for several. One male child has been reported to have a partial deletion of chromosome 18 but other complex rearrangements were also present.

An amino acid substitution (lysine) in the basic domain of the TWIST2 gene has been found in seven families in which ablepharon-macrostomia followed an autosomal dominant pattern.  Mutations in the same TWIST2 domain but leading to substitutions of glutamine or alanine amino acids is responsible for the Barber-Say phenotype (209885).

Mutations in the TWIST2 gene may also be responsible for Setleis syndrome (227260). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cosmetic surgery can correct at least some of the malformations. Vigorous effort may be required to maintain corneal surface wetting. 

References
Article Title: 

Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Marchegiani S, Davis T, Tessadori F, van Haaften G, Brancati F, Hoischen A, Huang H, Valkanas E, Pusey B, Schanze D, Venselaar H, Vulto-van Silfhout AT, Wolfe LA, Tifft CJ, Zerfas PM, Zambruno G, Kariminejad A, Sabbagh-Kermani F, Lee J, Tsokos MG, Lee CC, Ferraz V, da Silva EM, Stevens CA, Roche N, Bartsch O, Farndon P, Bermejo-Sanchez E, Brooks BP, Maduro V, Dallapiccola B, Ramos FJ, Chung HY, Le Caignec C, Martins F, Jacyk WK, Mazzanti L, Brunner HG, Bakkers J, Lin S, Malicdan MC, Boerkoel CF, Gahl WA, de Vries BB, van Haelst MM, Zenker M, Markello TC. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. Am J Hum Genet. 2015 Jul 2;97(1):99-110.

PubMed ID: 
26119818

Oculodentodigital Dysplasia

Clinical Characteristics
Ocular Features: 

The eyes have been reported as small and sometimes appear deep-set.  The epicanthal folds are prominent and the lid fissures are small.  Microcornea and evidence of anterior chamber dysplasia including posterior synechiae, anterior displacement of Schwalbe’s line, and stromal hypoplasia in the peripupillary area may be present.  Many eyes have some persistence of the pupillary membrane. Nystagmus and strabismus has been seen in some individuals.  A few patients have evidence of a persistent hyperplastic primary vitreous, even bilaterally. Cataracts may be present as well and a few patients have been reported with open angle glaucoma.  Most patients have normal or near normal visual acuity.

Systemic Features: 

The clinical features of this syndrome are highly variable.  Hair is sparse and the nails are usually dysplastic.  The nose appears small and peaked with underdevelopment of the nasal alae, and the mandible may be broad.  The cranial bones are often hyperostotic and the long bones as well as the ribs and clavicle are widened.  The middle phalanges of the digits are usually hypoplastic or may be absent.  Syndactyly of fingers and toes is often a feature and camptodactyly is common.  The teeth are small and carious with evidence of enamel dysplasia.   Hair often grows slowly and is sparse.  A variety of neurological deficits have been reported but no consistent pattern has been recognized.  However, white matter lesions and basal ganglia changes have been documented on MRI.

Genetics

Both autosomal recessive and autosomal dominant inheritance have been proposed but in both cases the mutations are in the same gene, GJA1, located at 6q21-q23.2.

This disorder is allelic to Hallermann-Streiff syndrome (234100).

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general condition is available.  Cataracts and glaucoma require attention when present, of course.

References
Article Title: 

Keratosis Follicularis Spinulosa Decalvans, X-Linked

Clinical Characteristics
Ocular Features: 

There is alopecia of the eyelashes and eyebrows.  The skin of the eyelids is thickened often with an associated chronic blepharitis followed by entropion (ectropion sometimes mentioned).  Photophobia and keratitis with 'corneal degeneration' are also features but it is unknown whether these are primary or secondary to trichiasis from the eyelid deformities.  The corneal findings usually precede the scarring alopecia of the scalp.

Systemic Features: 

Onset is in childhood.  Thickening of skin is generalized especially in the neck, ears, and the extremities with marked involvement of the palms and soles, especially in the calcaneal regions.  Scalp hair may be sparse, often in a streak pattern.  The follicles are inflamed and hyperkeratotic resulting in scarring alopecia.  Carriers have been reported to have dry skin with mild follicular hyperkeratosis and more extensive involvement of the soles.

Genetics

This is a rare disorder with genetic and clinical heterogeneity.  The majority of cases seem to be inherited in an X-linked recessive pattern secondary to mutations in the SAT1 gen located at Xp22.1.  Mutations in the MBTPS2 (Xp22.12) gene have also been identified.  However, multigenerational families with male to male transmission have also been reported suggesting autosomal dominant inheritance (KFSD; 612843).  However, no associated mutations or loci have been reported.

 

Pedigree: 
Autosomal dominant
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Retinoids reduce the inflammatory component and lead to cessation of the scalp alopecia.  A decrease in photophobia has also been reported but the clinical basis for this is unknown.

References
Article Title: 

Gene dosage of the spermidine/spermine N(1)-acetyltransferase ( SSAT) gene with putrescine accumulation in a patient with a Xp21.1p22.12 duplication and keratosis follicularis spinulosa decalvans (KFSD)

Gimelli G, Giglio S, Zuffardi O, Alhonen L, Suppola S, Cusano R, Lo Nigro C, Gatti R, Ravazzolo R, Seri M. Gene dosage of the spermidine/spermine N(1)-acetyltransferase ( SSAT) gene with putrescine accumulation in a patient with a Xp21.1p22.12 duplication and keratosis follicularis spinulosa decalvans (KFSD). Hum Genet. 2002 Sep;111(3):235-41.

PubMed ID: 
12215835

Rothmund-Thomson Syndrome

Clinical Characteristics
Ocular Features: 

Patients have been reported with juvenile and infantile cataracts.  Reported prevalence varies possibly because the diagnostic criteria have not been established and more than one disorder may be represented by the title.  Rothmund (an ophthalmologist) originally reported two families of 5 children in which lens opacities were found, but Thomson, who was a dermatologist, in a later report did not mention cataracts.  The lens opacities are usually nuclear or posterior cortical in location and may be evident in 50% of patients.  Iris stromal changes such as hypoplasia have also been reported.  Eyelashes and/or eyebrows may be sparse.  This is likely the same disorder as the previously described ‘mesodermal dysgenesis of the iris and skeletal dysplasia’ and formerly listed as 270240 in OMIM.

Systemic Features: 

This is a clinically heterogeneous disorder.  Skin atrophy with pigmentary changes, telangiectasia, short stature, premature aging, and skeletal abnormalities are characteristic.  There is an increased risk of malignancy, particularly osteosarcomas and skin cancer.  Saddle nose, sparse hair, hypogonadism, dysplastic nails, and teeth anomalies have also been described.

The skin is usually normal at birth but an erythematous rash typically appears in the first six months of life accompanied by swelling and blistering.  Eventually areas of hypo- and hyperpigmentation appear in a reticulated pattern with spots of punctate atrophy and telangiectasia.  Hyperkeratosis of the soles of the feet is common.  The skeletal abnormalities of dysplasia, radial ray defects, and missing bones are often evident at birth while osteopenia and delayed bone maturation are evident later.

Genetics

This is an autosomal recessive disorder in which most patients have mutations in the RECQL4 gene (8q24.3).

Mutations in the same gene cause Baller-Gerold syndrome (218600) suggesting that the two disorders are allelic but the phenotypes are considerably different.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the primary disorder but patients must be monitored for malignancies.  Visually significant cataracts should be removed.  It has been recommended that patients avoid excessive sun exposure to reduce the risk of skin cancers.

References
Article Title: 

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