hypogonadotropic hypogonadism

Bosma Arhinia Microphthalmia Syndrome

Clinical Characteristics
Ocular Features: 

Microphthalmia or clinical anophthalmia are usually present.  Iris colobomas are frequent features.  Occluded or absent nasolacrimal ducts have been reported.

Systemic Features: 

Arhina with anosmia is the most striking feature but it is usually accompanied by midface hypoplasia, a highly arched (or cleft) palate, and preauricular pits.  The nasal bones along with the cribriform plate, and other septal structures may be missing.  Maxillary and paranasal sinuses, together with the olfactory bulbs are often absent.  Intelligence is usually normal.

Choanal atresia is often present.  Hypogonadotropic hypogonadism with micropenis and cryptorchidism is an important feature in males.  Females may experience pubertal delay with menarche anomalies.  

Genetics

Heterozygous mutations in the SMCHD1 gene (18p11) are responsible for this disorder.  There is considerable clinical heterogeneity with many carriers having only minor manifestations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the general disorder has been described.

References
Article Title: 

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Gordon CT, Xue S, Yigit G, Filali H, Chen K, Rosin N, Yoshiura KI, Oufadem M, Beck TJ, McGowan R, Magee AC, Altmuller J, Dion C, Thiele H, Gurzau AD, Nurnberg P, Meschede D, Muhlbauer W, Okamoto N, Varghese V, Irving R, Sigaudy S, Williams D, Ahmed SF, Bonnard C, Kong MK, Ratbi I, Fejjal N, Fikri M, Elalaoui SC, Reigstad H, Bole-Feysot C, Nitschke P, Ragge N, Levy N, Tuncbilek G, Teo AS, Cunningham ML, Sefiani A, Kayserili H, Murphy JM, Chatdokmaiprai C, Hillmer AM, Wattanasirichaigoon D, Lyonnet S, Magdinier F, Javed A, Blewitt ME, Amiel J, Wollnik B, Reversade B. De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. Nat Genet. 2017 Feb;49(2):249-255.

PubMed ID: 
28067911

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 diagnosed in the first 5 years of life 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

Compund heterozygous mutations in PNPLA6 (19p13.2), coding for neuropathy target esterase, have been found in several patients presumed to have this 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.

Mutations in PNPLA6 occur in other conditions including a form of Bardet-Biedl Syndrome (209900), and Boucher-Neuhauser Syndrome (215470) also known as Chorioretinopathy, Ataxia, Hypogonadism Syndrome in this database.

Pedigree: 
Autosomal recessive
Treatment
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
Article Title: 

Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes

Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M, Anderson Y, Krueger LA, Gregory LC, Stoetzel C, Jaworek TJ, Hull S, Li A, Plagnol V, Willen CM, Morgan TM, Prows CA, Hegde RS, Riazuddin S, Grabowski GA, Richardson RJ, Dieterich K, Huang T, Revesz T, Martinez-Barbera JP, Sisk RA, Jefferies C, Houlden H, Dattani MT, Fink JK, Dollfus H, Moore AT, Ahmed ZM. Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet. 2015 Feb;52(2):85-94.

PubMed ID: 
25480986

Chorioretinopathy, Ataxia, and Hypogonadism

Clinical Characteristics
Ocular Features: 

The retinal pigment epithelium changes may be seen as early as the first decade of life with pigment deposition resembling bone spicules.  These changes as well as atrophy of the choriocapillaris are most apparent in the posterior pole and extend into the midperiphery.  Retinal vessels may be attenuated.  Progressive loss of vision, dyschromatopsia, and photophobia are the primary ocular symptoms. Night blindness and constricted visual fields are noted by some patients.  The ERG shows subnormal and sometimes absent photopic and scotopic responses.  Nystagmus is present in more than half of individuals. 

Systemic Features: 

Difficulties with balance, intention tremors, and scanning speech are evident in adolescence or early adult life.  Cerebellar ataxia is present in nearly 40 percent of individuals.  However, there is marked variability in the rate of progression.  Many patients have atrophy of the superior and dorsal areas of the cerebellar vermis and atrophy of the cerebellar hemispheres as noted on MRIs. Hypogonadotrophic hypogonadism is a feature with delayed puberty noted in 26 percent.  In the absence of exogenous hormone administration, secondary sexual characteristics fail to develop.

Genetics

Autosomal recessive inheritance has been suggested on the basis of consanguinity in three families, multiple affected sibs born to normal parents, and a 1:1 sex ratio.  Homozygous and compound heterozygous mutations in PNPLA6 (19p13.2) have been found in several patients.

Mutations in PNPLA6 occur in other conditions including a form of Bardet-Biedl Syndrome (209900), and Trichomegaly Plus Syndrome (275400), in this database.

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The use of appropriate hormones can stimulate the development of normal secondary sexual characteristics and may restore reproductive function.   At least two female patients gave birth to a child following hormone substitution.

Low vision aids could be helpful in selected patients.

References
Article Title: 

Boucher-Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature

Tarnutzer AA, Gerth-Kahlert C, Timmann D, Chang DI, Harmuth F, Bauer P, Straumann D, Synofzik M. Boucher-Neuhauser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature. J Neurol. 2014 Oct 31. [Epub ahead of print].

PubMed ID: 
25359264

PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum

Synofzik M, Gonzalez MA, Lourenco CM, Coutelier M, Haack TB, Rebelo A, Hannequin D, Strom TM, Prokisch H, Kernstock C, Durr A, Schols L, Lima-Martinez MM, Farooq A, Schule R, Stevanin G, Marques W Jr, Zuchner 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

Cataracts, Congenital, Facial Dysmorphism, and Neuropathy

Clinical Characteristics
Ocular Features: 

Cataracts, microphthalmia, and microcornea (mean diameter ~7.5 mm) are present at birth and precede the onset of neurological symptoms.  The lens opacities often consist of anterior and posterior subcapsular opacities but the entire lens may be opaque as well.  Some adults have bilateral ptosis.  The pupils are often small and have sluggish responses to light and mydriatics.  Strabismus and horizontal pendular nystagmus are common.  Visual impairment may be severe.

Systemic Features: 

The neuropathy is primarily motor and usually begins in the lower extremities but is progressive and eventually involves the arms as well.  Motor development is slow and walking is often unsteady from the start.  Speaking may not have its onset until 3 years of age.   Mild, nonprogresssive cognitive defects and mental retardation are often present.  Sensory neuropathy with numbness and tingling develops in the second decade.  Mild chorea, upper limb tremor, mild ataxia, and extensor plantar responses may be seen.  Deafness has been described.  Nerve conduction studies and biopsies have documented a demyelinating polyneuropathy while MRIs demonstrate cerebral and spinal cord atrophy which may be seen in the first decade of life.  The MRI in many patients reveals diffuse cerebral atrophy, enlargement of the lateral ventricles and focal lesions in subcortical white matter.  Most individuals have mild cognitive deficits while psychometric testing reveals borderline intelligence in a minority.

Patients are susceptible to acute rhabdomyolysis following viral infections.  Most are severely disabled by the third decade.

The facial dysmorphism appears in childhood and consists of a prominent midface, hypognathism, protruding teeth, and thickening of the lips.  Spinal deformities occur in the majority of individuals along with foot and hand claw deformities.  All patients are short in stature.  Hypogonadotropic hypogonadism is a common feature and females may be infertile.  Amenorrhea is often present by the age of 25-35 years.

Genetics

This is an autosomal recessive disorder found primarily among European Gypsies.  It is caused by mutations in the CTDP1 gene (18q23-qter).  It is sometimes confused with Marinesco-Sjogren syndrome (248800) with which it shares some clinical features but the two are genetically distinct.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts often require removal in the first decade of life. Scoliosis and foot deformities may benefit from surgical correction.  Supportive care and physical therapy can be helpful.

References
Article Title: 

Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome

Lagier-Tourenne C, Chaigne D, Gong J, Flori J, Mohr M, Ruh D, Christmann D, Flament J, Mandel JL, Koenig M, Dollfus H. Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome. J Med Genet. 2002 Nov;39(11):838-43.

PubMed ID: 
12414825

Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations

Tournev I, Kalaydjieva L, Youl B, Ishpekova B, Guergueltcheva V, Kamenov O, Katzarova M, Kamenov Z, Raicheva-Terzieva M, King RH, Romanski K, Petkov R, Schmarov A, Dimitrova G, Popova N, Uzunova M, Milanov S, Petrova J, Petkov Y, Kolarov G, Aneva L, Radeva O, Thomas PK. Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations. Ann Neurol. 1999 Jun;45(6):742-50.

PubMed ID: 
10360766

Galactokinase Deficiency

Clinical Characteristics
Ocular Features: 

This is a considerably more rare disorder of galactose metabolism compared with classic galactosemia (230400).  Both disorders cause cataracts in the neonatal period but the early systemic effects of galactokinase deficiency are less severe.  In the latter disorder, cataracts usually develop later, often during the first decade of life and less commonly during the neonatal period that is characteristic of classic galactosemia.  Galactitol  accumulation causing osmotic changes in the lens accounts for the cataracts and may also be responsible for the development of pseudotumor cerebri found infrequently.  Good dietary control may prevent the formation and progression of cataracts and it has been reported that they may regress as well but only prior to the rupture of cell membranes.

Systemic Features: 

Late complications include abnormalities in mental and/or motor development, dyspraxia, and hypogonadotropic hypogonadism which occur in spite of severe reduction in galactose intake.  Ovarian failure is common.

Genetics

This is an autosomal recessive disorder caused by mutations in the GALK1 gene (17q24) encoding galactokinase.  It is extremely rare but should be considered in any patient with cataracts found within the first two decades of life.  Deficient activity of the galactokinase enzyme can be demonstrated in erythrocytes.

For other disorders of galactose metabolism, see galactosemia (230400) and galactose epimerase deficiency (230350).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Early dietary restriction of non-galactose polycarbohydrates and deficient in lactose may prevent the formation of cataracts or sometimes result in regression.

References
Article Title: 

Galactosemia

Clinical Characteristics
Ocular Features: 

Neonatal cataracts are found among at least 30% of infants with this disorder.  However, early (before 17 days of age) dietary restrictions can prevent their formation or even lead to regression.  They result from the osmotic imbalance caused by the presence of accumulated galactitol.  Neonates may suffer vitreous hemorrhages from the coagulopathy but this is rare.

Systemic Features: 

In spite of early and adequate treatment, however, many adults have residual problems.  Cataracts have been found in 21%, decreased bone density in 24%, tremor in 46%, ataxia in 15%, and dysarthria in 24%.  Few patients of either sex have children and all females have premature ovarian insufficiency.  Depression and anxiety are present in 39-67%.  It has been estimated that there is a twofold increase in the odds of depression with each 10 year increment of age.

Genetics

This is an autosomal recessive disorder resulting from mutations in the GALT gene (9p13) encoding galactose-1-phosphate uridylyltransferase.

For other disorders of galactose metabolism see galactose epimerase deficiency (230350) and galactokinase deficiency (230200).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment with a lactose- and galactose-free diet within the first 3-17 days can prevent the formation of cataracts.  Few need surgical removal.  Liver function improves and a reduction in icterus can be seen.  It can also prevent fatal E. coli sepsis.  However, long term effects have been disappointing as many patients still develop mental and motor dysfunction as well as speech difficulties (dyspraxia).  The long term outcome seems to depend upon the level of GALT enzyme activity which varies considerably.

Special education and speech therapy may be beneficial.  Depression in older patients should be offered where indicated.

References
Article Title: 

The adult galactosemic phenotype

Waisbren SE, Potter NL, Gordon CM, Green RC, Greenstein P, Gubbels CS, Rubio-Gozalbo E, Schomer D, Welt C, Anastasoaie V, D'Anna K, Gentile J, Guo CY, Hecht L, Jackson R, Jansma BM, Li Y, Lip V, Miller DT, Murray M, Power L, Quinn N, Rohr F, Shen Y, Skinder-Meredith A, Timmers I, Tunick R, Wessel A, Wu BL, Levy H, Elsas L, Berry GT. The adult galactosemic phenotype. J Inherit Metab Dis. 2011 Jul 21. [Epub ahead of print]

PubMed ID: 
21779791
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