Hypogonadotrophic hypogonadism and GH deficiency in a man treated for Fanconi Anaemia
Fanconi Anaemia (FA) is an inherited bone marrow failure syndrome characterised by pancytopaenia, predisposition to malignancy and physical abnormalities such as short stature, microcephaly, developmental delay, and café au lait skin lesions. Most patients with FA develop bone marrow failure requiring haematopoietic stem cell transplantation [1].
FA is caused by mutations in one of at least 17 different FA genes. In most cases, FA is inherited in an autosomal recessive manner via either homozygous or compound heterozygous mutations affecting an individual FA gene. There are two rare subtypes which are exceptions to this, FANCB gene mutation is X linked recessive and FANCR which is autosomal dominant [1]. FA is a rare condition with an estimated incidence of 1in 100 000-250 000 live births [2].
There are a wide range of endocrine disorders associated with FA and approximately 80 % of individuals with FA have at least one endocrine abnormality. Often these results from anatomical disruption of the hypothalamic-pituitary axis during development such as pituitary stalk interruption and septo-optic dysplasia but they can also be caused by hematopoietic stem cell transplantation associated therapies [3]. Endocrine abnormalities include short stature, growth hormone deficiency, abnormal glucose metabolism, dyslipidaemia, hypothyroidism and pubertal delay [3].
We discuss a case of a 20 year old gentleman with FA with hypogonadotrophic hypogonadism, growth hormone deficiency, type 2 diabetes, and subclinical primary hypothyroidism. Diagnosis of FA was confirmed at age 4 with bone marrow aspirate and chromosome fragility testing and he underwent stem cell transplantation at age 7.
He had delayed growth and short stature. Growth hormone deficiency was confirmed with serum IGF 1 testing, growth hormone sleep study and arginine stimulation test. He received growth hormone treatment between ages 11 and 18 with daily somatotropin injections. His final height was 164cm, slightly below mid parental height and approximately the third 3rd centile for height. He had delayed puberty and received 6 months of testosterone therapy which was discontinued due to evidence of endogenous puberty.
When assessed at age 19, weight was 68kg giving him a body mass index of 25.3. Examination found reduced testicular volume (5-6 ml bilaterally by orchidometer), sparse facial hair and Tanner stage II pubic hair. There was biochemical evidence of hypogonadotrophic hypogonadism with early morning testosterone by LCMS 4.3 nmol/L and LH 3.9 mU/L, FSH 7 mU/L, SHGB 16nmol/L. After discussion with treating clinician, the patient opted not to pursue fertility or sperm analysis at present and has recently commenced testosterone replacement with testosterone gel.
Growth hormone deficiency has been demonstrated biochemically on multiple occasions most recently with a glucagon stimulation test, demonstrating undetectable GH levels at baseline and all intervals after.
In terms of other pituitary hormones, he not had cortisol insufficiency previously and a recent short synacthen test was normal. He has had evidence of subclinical primary hypothyroidism with most recent TSH of 6.4 mU/L and T4 13 pmol/L. Prolactin levels have been normal, most recently 120mU/L.
He has a history of type 2 diabetes, diagnosed at age 19, controlled with metformin and sitagliptin. He has had other manifestations of FA including conductive deafness, cleft palate and bony deformities of the hands and skull.
A recent MRI scan of the pituitary demonstrated dysgenesis of the corpus callosum with pronounced thinning of the corpus callosum body, mild thinning of the splenium, normal bulk of the genu and absence of the septum pellucidum. The pituitary stalk was present but thin and displaced to the
right, contiguous with a small volume of adenohypophysis in the sella. Optic nerves, chiasm and tracts with present, with mild volume loss. Features are consistent with septo-optic dysplasia.
Despite having radiological features of loss of volume in the optic chiasm and optic nerves, visual acuity has been normal and he has had normal visual fields to confrontation .
He is followed up regularly in Endocrinology and haematology clinic. He is not working at present and is studying a computing course part time.
Discussion
Fanconi Anaemia is a rare genetic disorder which has multiple systemic manifestations beyond the haematological abnormalities. Most patients with FA will experience at least one endocrine complication and screening for and managing endocrine conditions across the lifespan is an important aspect of FA management.
The patient discussed has anatomical disruption of the hypothalamic pituitary axis with septo-optic dysplasia and has had multiple endocrinopathies related to FA; growth hormone deficiency, delayed puberty and hypogonadism, type 2 diabetes, and subclinical primary hypothyroidism [3].
Many different abnormalities on MRI brain are described in FA and these include abnormalities of the pituitary, corpus callosum, posterior fossa and optic chiasm.
The patient discussed had a small pituitary gland, hypoplasia of the corpus callosum and mild volume loss of the optic nerves and optic chiasm. A small volume pituitary gland is a common radiological finding in FA and structural abnormalities of the hypothalamo-pituitary axis account for some but not all of the endocrinopathies in FA [5]. Septooptic dysplasia is a disorder of early brain development characterised by optic nerve hypoplasia, abnormal development of the structures separating the left of and right halves of the brain such as the corpus callosum and septum pellucidum and pituitary hypoplasia. Septoptic dysplasia has estimated incidence of 1 in 10 000 overall. Abnormalities in different genes involved in embroyonic development of the brain such as HESX1, OTX2 and SOX2 are associated with septo-optic dysplasia, though the genetics of the condition are not fully understood [9]. Septo-optic dysplasia is reported as a CNS manifestation of FA, though its prevalence among FA patients is not well known [5].
The etiology of primary hypothyroidism which occurs in 60% of patients with FA is unknown [6].
Key points
Endocrine abnormalities are common in patients Fanconi Anaemia with around 80 % having one or more endocrine disorder
Anatomical disruption of the hypothalamic –pituitary axis during development is common and can result in result in insufficiency of pituitary hormones - most often growth hormone and gonadotrophin deficiency
Primary thyroid dysfunction, metabolic syndrome and disorders of bone mineral metabolism are other important manifestations of FA.
Regular assessment of growth, glucose and lipid metabolism, thyroid function, cortisol, puberty and gonadal function and bone density are important parts of FA management.