growth hormone deficiency

Cataracts, Growth Hormone Deficiency, and Skeletal Dysplasia

Clinical Characteristics
Ocular Features: 

Lens opacities can be seen in infancy or childhood and may be congenital in onset.  Nystagmus has been noted in one patient. 

Systemic Features: 

There is considerable clinical heterogeneity in the phenotype.  Motor milestones may be slightly delayed.  Dysmorphic features in at least some individuals include bushy eyebrows, a prominent forehead, and a small mouth.  Thoracic scoliosis and genu valgum may be present.  Physical growth is reduced during infancy and childhood resulting in a short stature in adulthood.  Growth hormone and cortisol deficiency have been documented. Episodic hypoglycemia has been documented. The pituitary adenohypophysis appears atrophied on MRI.

Neurosensory hearing loss has been diagnosed in the first two years of life.  A distal sensory neuropathy with loss of pain, temperature and touch sensation may be present late in the first decade of life.  There are no cognitive deficits and patients can live independently.

Genetics

This is likely an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the IARS2 gene (1q41).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Appropriate hormonal replacement therapy can be beneficial.  Individual skeletal surgery for scoliosis and hip dislocation should be considered.  Visually significant lens opacities may require surgery.

References
Article Title: 

Mutation in The Nuclear-Encoded Mitochondrial Isoleucyl-tRNA Synthetase IARS2 in Patients with Cataracts, Growth Hormone Deficiency with Short Stature, Partial Sensorineural Deafness, and Peripheral Neuropathy or with Leigh Syndrome

Schwartzentruber J, Buhas D, Majewski J, Sasarman F, Papillon-Cavanagh S, Thiffaut I, Sheldon KM, Massicotte C, Patry L, Simon M, Zare AS, McKernan KJ; FORGE Canada Consortium, Michaud J, Boles RG, Deal CL, Desilets V, Shoubridge EA, Samuels ME. Mutation in The Nuclear-Encoded Mitochondrial Isoleucyl-tRNA Synthetase IARS2 in Patients with Cataracts, Growth Hormone Deficiency with Short Stature, Partial Sensorineural Deafness, and Peripheral Neuropathy or with Leigh Syndrome. Hum Mutat. 2014 Nov;35(11):1285-9.

PubMed ID: 
25130867

Septooptic Dysplasia

Clinical Characteristics
Ocular Features: 

Optic nerve hypoplasia is most characteristic ocular feature of this syndrome.  It may be bilateral but often is unilateral.  The hypoplastic nerve head can have a ‘double margin’.  The outer ring consists of the junction of the sclera with the lamina cribrosa while the inner margin is darker and represents the junction of the RPE with the abnormally small nerve containing less than the normal number of axons.  Visual acuity depends upon the degree of nerve hypoplasia.  Nystagmus and strabismus may be present. 

Systemic Features: 

Midline brain defects are common.  This usually consists of an absent septum pellucidum but sometimes absence or thinning of the corpus callosum as well.  An ‘empty sella’ with a dysplastic pituitary gland and deficiencies in hormone output can be present.  Hypoglycemia, hypogonadism, short stature and corticotrophin deficiency may result.  There is considerable clinical heterogeneity and few patients have all of these features.  Only 29% of patients have the full spectrum of brain, optic nerve, and pituitary abnormalities.  It has been proposed that the severity of the brain midline defects can be correlated with the degree of endocrinopathy.  Mental retardation and features of autism spectrum disorders may be present.

A few patients have been reported with skeletal deformities such as syndactyly and hypoplastic digits.  Rare males have underdeveloped genitalia. 

Genetics

The majority of cases occur sporadically.  Among rare cases with a family history, homozygosity of a mutation in the HESX1 gene (3p21.2-p21.1) has been found suggesting an autosomal recessive etiology.  It seems likely that there remains considerable genetic heterogeneity and it is doubtful that septooptic dysplasia is a unique disorder.  

Bilateral optic nerve hypoplasia (165550) also occurs without the CNS malformations but it results from a different mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

All patients with optic nerve hypoplasia should be evaluated for midline brain anomalies and endocrinopathy.  There is no treatment for the optic nerve hypoplasia but low vision aids could be helpful in selected cases with bilateral nerve dysplasia.  The hormonal deficiencies, of course, need to be corrected with appropriate replacements. 

References
Article Title: 

Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging

Birkebaek NH, Patel L, Wright NB, Grigg JR, Sinha S, Hall CM, Price DA, Lloyd IC, Clayton PE. Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab. 2003 Nov;88(11):5281-6.

PubMed ID: 
14602752
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