Extreme intra-familial variability of congenital central hypoventilation syndrome: a case series

Abstract

IntroductionCongenital central hypoventilation syndrome is an autosomal dominant disorder that classically presents as sudden death in infancy secondary to central hypoventilation. Most cases are caused by polyalanine repeat mutations in the paired-like homeobox 2B gene, PHOX2B. More severe disease is typically associated with nonpolyalanine repeat mutations. We report the case of a family with nonpolyalanine repeat mutations that uncharacteristically has many individuals who were mildly symptomatic and only diagnosed after genetic testing. We highlight the highly variable clinical presentation of this condition and the need for clinicians to remain vigilant.Case presentationWe identified 10 individuals in a large extended Caucasian family of German and Austrian background with congenital central hypoventilation syndrome.Case 1: A 16-year old male proband presented for reproductive counseling. He had a previous history of apneic spells and Hirschsprung disease in the neonatal period. A PHOX2B nonpolyalanine repeat mutation was identified in the proband and used to screen his extended family.Cases 2 to 10: Several mildly symptomatic family members (males aged 5, 13, 42 and 80 years; females aged 28, 44, 46 and 48 years) spanning four generations were identified after genetic screening. A newborn boy from this family was also recently diagnosed with Hirschsprung disease and went on to have an abnormal sleep study.ConclusionsIn this report, we highlight the significant phenotypic variability of congenital central hypoventilation syndrome, previously thought to be a rare genetic condition. Given the extreme clinical variability, it is possible that the prevalence of congenital central hypoventilation syndrome in the general population is much higher than previous estimates. This is of major importance to all clinicians who will need to maintain a high index of suspicion for this not so rare and highly clinically variable genetic condition that spans all ages. As the familial mutation has been identified, presymptomatic and prenatal diagnostic testing are available options for family members.

Three-Generation Family With Congenital Central Hypoventilation Syndrome and Novel PHOX2B Gene Non-Polyalanine Repeat Mutation

“…Approximately 10% of patients have a non-polyalanine repeat mutation (NPARM) in the PHOX2B gene, which is generally reported to be associated with a more severe phenotype. 1 Only a few familial cases of CCHS with confirmed PHOX2B gene mutations have been previously reported in the literature, [2][3][4][5][6][7] only two of which involve the PHOX2B NPARM mutation. 4,5 In these two familial cases, Hirschsprung disease as well as respiratory control symptoms were prominent.…”

Significant phenotype variability of congenital central hypoventilation syndrome in a family with polyalanine expansion mutation of the PHOX2B gene

“…Just five familial cases with proved PHOX2B gene mutation expressed in more than two generations have been described so far (ref. [14][15][16][17][18] ). Therefore, we reviewed them through PubMed search in (Table 1).…”

Congenital Central Hypoventilation Syndrome: A Comprehensive Review and Future Challenges

“…Laboratories from the United States, France, Chile, Italy, Japan, Germany, China, Taiwan, The Netherlands, the UK, and Australia have now collectively diagnosed nearly 1000 cases by PHOX2B mutation-confirmed CCHS [1]. It is estimated that the actual prevalence is much higher due to the extreme clinical variability [2][3][4]. The male to female ratio is estimated to be 1 : 1 [5].…”

“…This predisposes a range of autonomic aberrations in addition to the loss of ventilatory drive during sleep, resulting in reduced CO 2 and O 2 sensitivity [16]. Two types of mutations in this gene have been described: polyalanine repeat mutations (PARMs) have a variable clinical presentation and the disease's severity correlates with allele size and nonpolyalanine repeat mutations (NPARMS) which are usually associated with a more severe presentation including Hirschsprung's disease and an increased tumor risk [4,17,18]. Milder forms of CCHS are due to smaller PARMs and have also been described [19][20][21].…”

“…These mutations mostly occur de novo during gametogenesis although in some cases there is a possibility of inheritance from parents with somatic mosaicism or constitutive mutation. The disease has an autosomal dominant mode of inheritance (with incomplete penetrance) [4,28]. CCHS more commonly presents itself in neonates and later onset cases have occurred up to the age of 10 years [29].…”