Endocrine abnormalities in cardiofaciocutaneous syndrome: a case of precocious puberty, hyperprolactinemia and diabetes insipidus

Abstract

A 7-year-8-month-old boy with cardiofaciocutaneous syndrome caused by the D638E mutation of the B-Raf proto-oncogene (BRAF) presented with new-onset seizures. He was incidentally found to have advanced Tanner staging on physical examination. Hormonal testing revealed pubertal levels of gonadotropins and sex steroid hormones. On brain imaging, a lack of visualisation of the posterior pituitary bright spot was observed, in addition to mild thinning of the corpus callosum and the lateral gyri of the cerebellar hemispheres. A diagnosis of idiopathic central precocious puberty was made and the patient was started on leuprolide depot treatment. Pituitary hormone testing revealed hyperprolactinemia for which the patient did not receive treatment as he was asymptomatic. During a subsequent hospital admission for seizures, the patient was diagnosed with transient central diabetes insipidus for which he required treatment with a desmopressin infusion.

Background

Cardiofaciocutaneous syndrome (CFCS) is a rare multiple congenital anomaly disorder that affects several hundred people worldwide.¹ It is characterised by dysmorphic craniofacial features, congenital heart disease, dermatological abnormalities, failure to thrive, moderate to severe developmental delay as well as gastrointestinal tract and central nervous system anomalies.^{2 3} Craniofacial features include a large forehead with bitemporal narrowing, hypertelorism, downward-slanting palpebral fissures with epicanthic folds and a short broad nose.³ Dermatological findings most commonly consist of keratosis pilaris, sparse or absent eyebrows, multiple pigmented nevi, and sparse and curly hair.^{2 3} Cardiac problems include pulmonary valvular stenosis, atrial septal defect and hypertrophic cardiomyopathy.^{2 3} Neurocognitive delay and seizures are common. Brain imaging studies have identified multiple structural brain anomalies, including ventriculomegaly, hydrocephalus, cortical and brainstem atrophy, corpus callosum hypoplasia and abnormal myelination.^{2 3} Endocrinological abnormalities include failure to thrive, short stature, growth hormone (GH) deficiency or resistance and delayed puberty.²

CFCS is caused by de novo autosomal dominant germline mutations of genes in the Ras/mitogen-activated protein kinase (MAPK) pathway, which is involved in cell cycle regulation, differentiation and senescence. Mutations have been identified in four genes: B-Raf proto-oncogene (BRAF), mitogen-activated protein kinase kinase 1 (MAP2K1 (MEK1)), mitogen-activated protein kinase kinase 2 (MAP2K2 (MEK2)) and KRAS proto-oncogene (KRAS).⁴ Although the prognosis of CFCS remains unknown, the average life expectancy may be shortened due to cardiac abnormalities.^{2 3} Due to the many aspects of CFCS, multidisciplinary care including specialists in the fields of genetics, cardiology, dermatology, neurology, gastroenterology, endocrinology as well as physical and occupational therapy is essential.² In the current literature, there is only a limited amount of material examining the endocrine abnormalities associated with CFCS.

Case presentation

The patient is a 7-year-8-month-old boy who was born at term with a perinatal history of meconium aspiration. The patient is known for CFCS caused by the D638E mutation in the BRAF gene that has been previously reported in a patient with CFCS.⁵ The patient possesses several of the craniofacial and cutaneous features characteristic of CFCS, including bitemporal narrowing, a short broad nose, and sparse and curly hair. The patient does not have any of the cardiac abnormalities typically seen in CFCS. The patient is also known for gastro-oesophageal reflux, failure to thrive, short stature with a height below the third percentile for age and severe global developmental delay. The patient has undergone several surgeries, including laryngeal cleft repair, supraglottoplasty, strabismus correction, myringotomy and tympanostomy, adenoidectomy and gastrostomy tube placement due to feeding difficulties. There is no pertinent family history.

The patient developed new onset seizures and was admitted for treatment of status epilepticus. Due to a lack of visualisation of the posterior pituitary bright spot on brain MRI, as seen in figure 1, an endocrine workup was initiated, in particular for diabetes insipidus. Physical examination revealed Tanner stage 2 pubic hair, an enlarged penis of Tanner stage 3 and enlarged testes of 8–10 cc bilaterally.

Figure 1.

Sagittal brain MRI. There is a lack of visualisation of the posterior pituitary bright spot, in addition to mild thinning of the corpus callosum and the lateral gyri of the cerebellar hemispheres.

Investigations

An electroencephalogram was performed as part of the investigations of new-onset seizures, which showed focal right parietal activity.

Gonadotropin and sex steroid hormone testing revealed pubertal levels of luteinising hormone (LH, 2.2 IU/L vs reference range <1.2 IU/L) and testosterone (4.41 nmol/L vs <0.8 nmol/L). Prolactin was found to be elevated (138.2 µg/L vs 0.0–18.0 µg/L). Thyroid stimulating hormone and free thyroxine were normal. Insulin-like growth factor 1 (IGF-1), which is an indirect measurement of GH secretion, was normal. Beta human chorionic gonadotropin and carcinoembryonic antigen were measured as part of the precocious puberty workup and were normal.

The patient was hypernatremic on two occasions, at 150 and 148 mmol/L (reference range 137–144 mmol/L), but the urine output was normal (1.7 mL/kg/hour) and simultaneous urine osmolalities were 627 and 592 mOsm/kg, respectively, indicating good ability to produce concentrated urine.

Differential diagnosis

The baseline pubertal value of LH, in combination with pubertal testicular enlargement, is indicative of central precocious puberty. The brain MRI did not show any findings of structural abnormalities other than a faint posterior bright spot, which led to the diagnosis of idiopathic central precocious puberty.

An elevated prolactin level was detected during anterior pituitary hormone testing. Pathological causes of hyperprolactinemia include pituitary prolactinomas, as well as hypothalamic tumours and hypothalamic–pituitary stalk damage that disrupt the dopaminergic inhibition of prolactin secretion.⁶ Brain imaging excluded these potential causes, although the possibility of a microadenoma too small to be detected cannot be eliminated. Hyperprolactinemia may also be drug-induced. The patient had been prescribed domperidone, which acts as a dopamine receptor antagonist. However, it is unlikely for this degree of hyperprolactinemia to be solely drug-induced.⁷

In regard to the workup for diabetes insipidus, the absence of polyuria and the ability to produce moderately concentrated urine made the diagnosis of central diabetes insipidus unlikely, although the possibility of partial central diabetes insipidus could not be definitively excluded.

Treatment

Status epilepticus was treated with multiple doses of intravenous midazolam and the patient was then started on a combination of levetiracetam, phenobarbital and valproic acid. Several anticonvulsants are often required to control refractory seizures in CFCS.² The patient was started on monthly leuprolide depot intramuscular injections at a dose of 7.5 µg as treatment for precocious puberty. No treatment was initiated for asymptomatic hyperprolactinemia.

Outcome and follow-up

One month following the initiation of treatment, testosterone went from a mid-pubertal level of 4.41 nmol/L to an early pubertal level of 1.43 nmol/L. Repeated urine osmolality was 907 mOsm/kg, making the possibility of partial central diabetes insipidus increasingly unlikely. A repeated prolactin level remained elevated at 153.5 µg/L; however, the patient remained asymptomatic and therefore treatment was not indicated. At the 3-month follow-up visit, the testicular volumes had decreased to 4–5 and 5–6 cc. The monthly leuprolide depot injections were continued at the same dose. The testosterone level decreased to a near pre-pubertal level of 0.93 nmol/L and the gonadotropin levels decreased as expected.

Four months following diagnosis, the patient was readmitted to the hospital for treatment of status epilepticus following an anticonvulsant weaning attempt. During the admission, the patient developed polyuria (10 mL/kg/hour), hypernatremia with serum sodium levels reaching 159 mmol/L and elevated calculated serum osmolality values up to 328 mOsm/kg. Simultaneous urine concentration reached a maximum measured value of only 367 mOsm/kg. The patient was diagnosed with diabetes insipidus, likely related to the poorly visualised posterior pituitary bright spot on brain MRI. The patient responded appropriately to a 3-day long desmopressin infusion, confirming the diagnosis of central diabetes insipidus, which turned out to be transient and did not require further desmopressin treatment.

Discussion

Since CFCS was first described by Reynolds et al in 1986, there have been five reported cases of patients with CFCS diagnosed with precocious puberty.⁸ A 2006 publication reported a 7-year-old boy with precocious puberty who was later found to have a BRAF mutation.⁹ In 2008, Armour and Allanson found one case of precocious puberty in a cohort of 38 patients with CFCS with confirmed mutations. However, no data were provided regarding the age, gender or mutation type.¹⁰ In 2014, the case of a 7-year-6-month-old boy with a MEK1 mutation with precocious puberty, GH deficiency and hyperprolactinemia was published. The patient had normal brain and pituitary gland imaging. To the authors' knowledge, this was the first reported case of CFCS and hyperprolactinemia.¹¹ In 2016, a retrospective chart review of two patients with CFCS and two patients with Costello syndrome who presented with precocious puberty was performed. One of the patients with CFCS was a 4-year-old boy with a BRAF mutation and the other was a 3-year-old girl with a KRAS mutation.¹²

This is the first published case to date of CFCS and diabetes insipidus, the second case of CFCS and hyperprolactinemia, and the sixth case of CFCS and precocious puberty. Including this case, four of the five patients with CFCS with precocious puberty for whom clinical data are available, are  male. This is remarkable, given the overwhelming preponderance of women with precocious puberty compared with men in the general population. In central precocious puberty, the female to male ratio has been reported to be as high as 23:1.¹³Compared with girls, boys have a higher incidence of precocious puberty due to central nervous system disorders, including tumours and hamartomas.¹⁴ However, the four patients with CFCS with precocious puberty for whom brain imaging information was available, had no structural abnormalities, apart from one patient with mild ventricular asymmetry and non-specific thinning of the corpus callosum, as well as the imaging findings of our patient, which have been previously described in CFCS.^{9 11 12} The possibility of increasing the understanding of the control of pubertal timing through the study of patients with RASopathies has already been recognised.¹² The preponderance of precocious puberty among male patients with CFCS, pointed for the first time here, may provide additional clues towards the understanding of the sex difference seen in the prevalence of precocious puberty.

Management guidelines for CFCS must adequately address the associated endocrine abnormalities in order to ensure optimal patient care. A recent report on the best practices of care highlights failure to thrive, short stature, GH deficiency, GH resistance and delayed puberty in regard to the associated endocrine disorders. The current management recommendations suggest referral to an endocrinologist for growth monitoring between the age of 2–3 years (or earlier if there are growth concerns), measurement of thyrotropin, free thyroxine, IGF-1 and IGF-binding protein 3 levels, and annual monitoring of Tanner staging beginning at 10 years of age.² The guidelines must be updated to include earlier monitoring for precocious puberty, and possibly hyperprolactinemia and diabetes insipidus as well.

Learning points.

• Cardiofaciocutaneous syndrome (CFCS) is associated with important endocrine abnormalities, including, but not limited to, precocious puberty, hyperprolactinemia and now diabetes insipidus.

• Future studies of the Ras/MAPK pathway may help advance understanding of pubertal timing and of sex differences seen in the prevalence of precocious puberty.

• Current management guidelines for CFCS must be updated to adequately address the associated endocrine abnormalities and to ensure timely endocrinology workup as needed.