Structural pituitary abnormalities associated with CHARGE syndrome

Abstract

Introduction: CHARGE syndrome is a multisystem disorder that, in addition to Kallmann syndrome/isolated hypogonadotrophic hypogonadism, has been associated with anterior pituitary hypoplasia (APH). However, structural abnormalities such as an ectopic posterior pituitary (EPP) have not yet been described in such patients.

Objective: The aims of the study were: 1) to describe the association between CHARGE syndrome and a structurally abnormal pituitary gland; and 2) to investigate whether CHD7 variants, which are identified in 65% of CHARGE patients, are common in septo-optic dysplasia /hypopituitarism.

Methods: We describe 2 patients with features of CHARGE and EPP. CHD7 was sequenced in these and other patients with septo-optic dysplasia/hypopituitarism.

Results: EPP, APH, and GH, TSH, and probable LH/FSH deficiency were present in 1 patient, and EPP and APH with GH, TSH, LH/FSH, and ACTH deficiency were present in another patient, both of whom had features of CHARGE syndrome. Both had variations in CHD7 that were novel and undetected in control cohorts or in the international database of CHARGE patients, but were also present in their unaffected mothers. No CHD7 variants were detected in the patients with septo-optic dysplasia/hypopituitarism without additional CHARGE features.

Conclusion: We report a novel association between CHARGE syndrome and structural abnormalities of the pituitary gland in 2 patients with variations in CHD7 that are of unknown significance. However, CHD7 mutations are an uncommon cause of septo-optic dysplasia or hypopituitarism. Our data suggest the need for evaluation of pituitary function/anatomy in patients with CHARGE syndrome.

Figure 1.

A, A CHD7 mutation associated with CHARGE syndrome and hypopituitarism. A total of 102 patients with hypopituitarism including 2 with additional features of CHARGE syndrome were screened for CHD7 mutations. A novel heterozygous missense mutation (c.2194C>G, p.P732A) was identified in exon 4 in a Caucasian male patient with probable CHARGE syndrome and hypopituitarism (shown by arrow). B, An intronic CHD7 mutation associated with CHARGE syndrome and hypopituitarism. A heterozygous mutation (c.IVS35+6T>C) was found 6 bases 3′ of exon 35 in a Caucasian male patient with CHARGE syndrome and hypopituitarism (shown by arrow). C, The conservation of CHD7 p.P372. The proline amino acid (represented by the green 'P') at location p.P732 is highly conserved between multiple species. In patient 1, this proline was substituted by alanine. D, Schematic diagram of the CHD7 gene showing the location of both mutations (arrows). The P732A mutation is located before the first Chromo domain in the CHD7 gene (indicated by the first black arrow). The c.IVS35+6T>C is located late in the first BRK domain in a proposed splicing region (indicated by the second black arrow).

Figure 2.

A, MRI in patient 1 revealed APH, an absent pituitary stalk (APS) with an undescended/EPP at the tuber cinereum and a thin corpus callosum. B, Growth chart for patient 1 and the sister of patient 1. Patient 1 presented with short stature at the age of 3 years and was commenced on GH at 7 years of age (left arrow). The sister of patient 1 was found to be GH deficient at 6 years of age. F, father; M, mother; MPH, midparental height. C, Photographs of patient 1 and his sister. Left, Patient 1 with probable/possible CHARGE syndrome according to Blake criteria. Right, The sister of patient 1 with an atrial septum defect (APS), abnormal ear, squint, developmental delay, and GHD. D, MRI of patient 2 at 2 months (left) and 20 months of age (right) revealed APH and an APS with an EPP at the tuber cinereum, bilateral colobomata, and underdeveloped frontal lobes. E, Growth chart of patient 2. Patient 2 presented with short stature at the age of 3 years and has recently been commenced on GH treatment at the age of 3 years (arrow).