frontal bossing

Trichomegaly Plus Syndrome

Clinical Characteristics

Ocular Features

Eyelashes are described as ‘long’, and the eyebrows are bushy.  The majority of individuals have poor vision secondary to severe receptor dysfunction.  Night blindness and severe photophobia are features in some cases.  Both retinal and choroidal atrophy have been reported and most patients have a progressive and extensive pigmentary retinopathy.

Systemic Features

Scalp alopecia and sparse body hair is common in spite of the trichomegaly of the eyebrows and eyelashes.  Frontal bossing has been noted in some patients.  Pituitary dysfunction is suggested by low growth hormone levels, features of hypogonadotropic hypogonadism, and possibly hypothyroidism.

Some deficit of cognitive function is usually present and a few patients have been described as mentally retarded.  There is evidence of progressive neurological damage both centrally and peripherally. Developmental milestones are often achieved late and some individuals have been observed to regress during the first decade of life.  The peripheral neuropathy includes both sensory and motor components.  Sensory nerve action potentials may be lost in the first decade while early motor functions may regress during the same period.  Several patients have had evidence of progressive cerebellar ataxia.

Genetics

No locus or mutation has been found in this rare condition.  Autosomal recessive inheritance has been proposed on the basis of a single family in which an affected brother and sister were born to first cousin parents.   

The relationship of this disorder to that found in two cousins, offspring of consanguineous matings, described as ‘cone-rod congenital amaurosis associated with congenital hypertrichosis: an autosomal recessive condition’ (204110 ) is unknown.  They were described as having visual impairment from birth and profound photophobia.  Fundus changes were minimal with a bull’s eye pattern of pigment changes in the macula described as indicative of a rod-cone congenital amaurosis.  ERG responses were unrecordable.  These individuals apparently did not have other somatic, psychomotor or neurologic deficits.

Treatment Options

No treatment is available for this condition although growth hormone and testosterone supplementation have been reported to have the appropriate selective effects.

References

Sonmez S, Forsyth RJ, Matthews DS, Clarke M, Splitt M. Oliver-McFarlane syndrome (chorioretinopathy-pituitary dysfunction) with prominent early pituitary dysfunction: differentiation from choroideremia-hypopituitarism. Clin Dysmorphol. 2008 Oct;17(4):265-7.

PubMed ID: 
18978655

Haimi M, Gershoni-Baruch R. Autosomal recessive Oliver-McFarlane syndrome: retinitis pigmentosa, short stature (GH deficiency), trichomegaly, and hair anomalies or CPD syndrome (chorioretinopathy-pituitary dysfunction). Am J Med Genet A. 2005 Oct 15;138A(3):268-71.

PubMed ID: 
16155639

Jalili IK. Cone-rod congenital amaurosis associated with congenital hypertrichosis: an autosomal recessive condition. J Med Genet. 1989 Aug;26(8):504-10.

PubMed ID: 
2769722

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.  The presence of parental consanguinity in many families suggests autosomal recessive inheritance but no mutation or gene has been described.

Treatment Options

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

References

Bozkurt B, Yildirim MS, Okka M, Bitirgen G. GAPO syndrome: four new patients with congenital glaucoma and myelinated retinal nerve fiber layer. Am J Med Genet A. 2013 Apr;161(4):829-34.

PubMed ID: 
23494824

Bacon W, Hall RK, Roset JP, Boukari A, Tenenbaum H, Walter B. GAPO syndrome: a new case of this rare syndrome and a review of the relative importance of different phenotypic features in diagnosis. J Craniofac Genet Dev Biol. 1999 Oct-Dec;19(4):189-200. Review.

PubMed ID: 
10731088

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

PubMed ID: 
10197743

Adrenoleukodystrophy, Autosomal

Clinical Characteristics

Ocular Features

This early onset and rapidly progressive form of adrenoleukodystrophy is rare.  The early onset and rapidly fatal course of the disease has limited full delineation of the ocular features.  The most striking is the presence of ‘leopard-spots’ pigmentary changes in the retina.  Polar cataracts, strabismus, and epicanthal folds have also been reported. 

Systemic Features

Onset of symptoms occurs shortly after birth often with seizures and evidence of psychomotor deficits.  Rapid neurologic deterioration begins at about 1 year of age with death usually by the age of 3 years.  Hyperpigmentation of the skin may be apparent a few months after birth.  Opisthotonus has been observed.  The ears may be low-set, the palate is highly arched, and the nostrils anteverted.  Frontal bossing may be present.  Serum pipecolic acid and very-long-chain fatty acids (VLCFAs) can be markedly elevated.  Cystic changes in the kidneys have been reported. 

Genetics

This is an autosomal recessive peroxismal disorder resulting from homozygous mutations in receptor gene mutations such as PEX1, PEX5, PEX13, and PEX26.

There is also an X-linked recessive adrenoleukodystrophy (300100) sometimes called ALD but it lacks some of the morphologic features and is somewhat less aggressive. 

Neonatal adrenoleukodystrophy along with infantile Refsum disease (266510, 601539) and Zellweger syndrome (214100) are now classified as Zellweger spectrum or perioxismal biogenesis disorders.

Treatment Options

Treatment is mainly supportive for associated health problems. 

References

Chen WW, Watkins PA, Osumi T, Hashimoto T, Moser HW. Peroxisomal beta-oxidation enzyme proteins in adrenoleukodystrophy: distinction between X-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy. Proc Natl AcadSci U S A. 1987 Mar;84(5):1425-8.

PubMed ID: 
3469675

Cohen SM, Green WR, de la Cruz ZC, Brown FR 3rd, Moser HW, Luckenbach MW, Dove DJ, Maumenee IH. Ocular histopathologic studies of neonatal and childhood adrenoleukodystrophy. Am J Ophthalmol. 1983 Jan;95(1):82-96.

PubMed ID: 
6295171

Hallermann-Streiff Syndrome

Clinical Characteristics

Ocular Features

Nearly all patients (80+ %) have microphthalmia and bilateral congenital cataracts.  The eyebrows may be hypoplastic and the eyelashes likewise are sparse.  The lid fissures often slant down and telecanthus has been noted.  The distance between the two eyes appears reduced.  Blue sclerae, nystagmus, strabismus, and glaucoma are present in 10 to 30% of patients.

Systemic Features

The facies are sometimes described as ‘bird-like’ with a beaked nose, brachycephaly, and micrognathia.  Microstomia with a shortened ramus and forward displacement of the termporomandibular joints is characteristic. Upper airway obstruction may occur with severe respiratory distress.  The forehead is relatively prominent, the palate is highly arched, and the teeth are often small and some may be missing with misalignment of others.  A few teeth may even be present at birth (natal teeth).  Children appear petite and are often short in stature.  Scalp hair is thin, especially in the frontal and occipital areas, and the skin is atrophic.  Developmental delays are common but most patients have normal or near-normal intelligence.

Genetics

Most cases are sporadic but some have mutations in the GJA1 gene (6q21-q23.2).  Both autosomal dominant and autosomal recessive inheritance have been postulated.  Reproductive fitness may be low but rare affected individuals have had affected offspring.  Males and females are equally affected.

This disorder is allelic to oculodentodigital dysplasia (257850, 164200).

Treatment Options

Airway obstruction may require intervention and its risks must be considered during administration of general anesthesia.  Lens opacification may be severe even early in life and requires prompt surgical intervention to prevent amblyopia.

References

Cohen MM Jr. Hallermann-Streiff syndrome: a review. Am J Med Genet. 1991 Dec 15;41(4):488-99. Review.

PubMed ID: 
1776643

Salbert BA, Stevens CA, Spence JE. Tracheomalacia in Hallermann-Streiff syndrome. Am J Med Genet. 1991 Dec 15;41(4):521-3.

PubMed ID: 
1776648

Chondrodysplasia Punctata 2

Clinical Characteristics

Ocular Features

Early onset cataracts, often sectorial, are the major ocular feature of this syndrome.  There may be local vitreoretinal abnormalities leading to localized detachments and retinoschisis.

Systemic Features

The cartilage disease in this disorder leads to short stature that is often asymmetrical.  There is considerable variation in skeletal manifestations as the spine as well as the limbs can be involved.  The skin at birth may be scaly and erythrodermic.  Later the skin pigmentation may assume a whorled pattern and hyperkeratosis appears, often in a segmental pattern consistent with X-chromosomal mosaicism.  The skin may also be ichthyotic.  The nasal bridge is often flat with frontal bossing.  Flexion contractures are sometimes seen.  Cicatricial alopecia and coarse hair are often noted in adults.

Genetics

A number of skeletal disorders are classified as chondrodysplasia punctata, and there is considerable clinical and genetic heterogeneity (see also rhizomelic chondrodysplasia punctata [215100] in this database for an autosomal recessive form) which has yet to be worked out.  The disorder described here is an X-linked dominant disorder with lethality in males.  It results from a mutation in the EBP gene (Xp11.23-p11.22) causing difficulty in converting lanosterol to cholesterol.  The diagnosis can be confirmed by finding increased plasma accumulation of precursors of sterols 8(9)-cholestenol and 8-dehydrocholesterol. Rare severely affected males have been reported. 

The X-linked recessive (CDPX1;302950), autosomal dominant tibia-metacarpal (118651), and humero-metacarpal types are not associated with cataracts.

Treatment Options

Cataract extraction may improve vision.

References

Ausavarat S, Tanpaiboon P, Tongkobpetch S, Suphapeetiporn K, Shotelersuk V. Two novel EBP mutations in Conradi-Hünermann-Happle syndrome. Eur J Dermatol. 2008 Jul-Aug;18(4):391-3.

PubMed ID: 
18573709

Kalter DC, Atherton DJ, Clayton PT. X-linked dominant Conradi-Hünermann syndrome presenting as congenital erythroderma. J Am Acad Dermatol. 1989 Aug;21(2 Pt 1):248-56.

PubMed ID: 
2527874

Happle R. X-linked dominant chondrodysplasia punctata. Review of literature and report of a case. Hum Genet. 1979;53(1):65-73.

PubMed ID: 
535904

Basal Cell Nevus Syndrome

Clinical Characteristics

Ocular Features

Eyelid basal-cell carcinomas are the most common ocular finding of this syndrome.  These malignancies may be multiple and may occur on the neck, chest, back, arms and elsewhere on the face.   Those on the eyelids generally have their onset in the postpubertal period, usually by age 35 years, and are often multiple.  Their indolent nature can result in considerably delay in diagnosis, however, and local recurrences are common.  Deformities of the skull often result in the appearance of hypertelorism and proptosis.  Epidermal cysts are found in one-fourth of patients, especially on the palms, but may occur in the tarsal conjunctiva as well.  Less common reported ocular findings are colobomas, glaucoma, nystagmus, strabismus, and cataracts but these may simply be associations.

Systemic Features

This disorder is one of a few in which a disposition to neoplasia is associated with skeletal deformities.  These include bifid ribs, scoliosis, skull deformities such as frontal bossing, increased occipitofrontal circumference, broad nasal root with hypertelorism, mandibular prognathia, and bony cysts.  Medulloblastoma is an infrequent but important sign.  Palmar and/or plantar pits are often present.  Basal cell carcinomas and jaw cysts occur in over 90% of patients by the age of 40 years.  Invasive oral tumors are found in 78% of individuals.

Genetics

This is an autosomal dominant disorder, caused by mutations in the PTCH1 gene located on chromosome 9 (9q22.3).  Interestingly, somatic mutations in the PTCH1 gene have also been found in isolated cases with only basal cell carcinoma or medulloblastoma.  Perhaps 40% of cases arise de novo, i.e., without a family history, and older paternal age at conception increases the risk of new mutations.

Treatment Options

Treatment is directed at the location of clinical disease with excision of basal cell carcinomas having the highest priority.  Patients must be monitored throughout life for new lesions as well as recurrence at treated sites. Radiotherapy and non-essential diagnostic X-rays should probably be avoided due to sensitivity to ionizing radiation.

Oral administration of an experimental small molecule signaling inhibitor (GDC-0449 or Vismodegib; Genetech) of the Hedgehog signaling pathway has shown promise in reduction of the number of new lesions as well as shrinkage of existing skin lesions.

References

Goldberg LH, Firoz BF, Weiss GJ, Blaydorn L, Jameson G, Von Hoff DD. Basal cell nevus syndrome: a brave new world. Arch Dermatol. 2010 Jan;146(1):17-9. PubMed PMID: 20083687.

PubMed ID: 
20083687

Lo Muzio L. Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis. 2008 Nov 25;3:32. Review.

PubMed ID: 
19032739

Honavar SG, Shields JA, Shields CL, Eagle RC Jr, Demirci H, Mahmood EZ. Basal cell carcinoma of the eyelid associated with Gorlin-Goltz syndrome. Ophthalmology. 2001 Jun;108(6):1115-23.

PubMed ID: 
11382639

Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, Bale AE, Bale SJ. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. 1997 Mar 31;69(3):299-308.

PubMed ID: 
9096761

Levine DJ, Robertson DB, Varma VA. Familial subconjunctival epithelial cysts associated with the nevoid basal cell carcinoma syndrome. Arch Dermatol. 1987 Jan;123(1):23-4.

PubMed ID: 
3800416

Neuhauser Syndrome

Clinical Characteristics

Ocular Features

This rare disorder is characterized by profound mental retardation and megalocornea together with nonspecific facial features including epicanthal folds, broad nasal root, frontal bossing and antimongoloid lid slanting.

Systemic Features

Hypotonia and marked psychomotor retardation are the most prominent systemic features.   Short stature, hypercholesterolemia, seizures and hypothyroidism have also been reported.

Genetics

No specific mutation has been found.  Most cases occur sporadically.  The mode of inheritance is presumed to be autosomal recessive on the basis of parental consanquinity found in occasional parents with multiple affected offspring.

Treatment Options

No treatment is available.
 

References

Synofzik M, Gonzalez MA, Lourenco CM, Coutelier M, Haack TB, Rebelo A, Hannequin D, Strom TM, Prokisch H, Kernstock C, Durr A, Schöls L, Lima-Martínez MM, Farooq A, Schüle R, Stevanin G, Marques W Jr, Züchner S. PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain. 2013 Dec 19. [Epub ahead of print].

PubMed ID: 
24355708

Neuhäuser G, Kaveggia EG, France TD, Opitz JM. Syndrome of mental retardation, seizures, hypotonic cerebral palsy and megalocorneae, recessively inherited. Z.Kinderheilkd. 1975 Jul 1;120(1):1-18.

PubMed ID: 
1172332

Verloes, A.; Journel, H.; Elmer, C.; Misson, J.-P.; Le Merrer, M.; Kaplan, J.; Van Maldergem, L.; Deconinck, H.; Meire, F. : Heterogeneity versus variability in megalocornea-mental retardation (MMR) syndromes: report of new cases and delineation of 4 probable types.  Am. J. Med. Genet. 46: 132-137, 1993.

PubMed ID: 
8484397