Abstract
This is a report of a 36 week male infant who suffered abdominal distension and difficulty opening bowels within first few days of life and showed a pattern of hypoventilation and apnea associated with sleep. His diagnostic studies confirmed the diagnosis of congenital central hypoventilation syndrome CCHS (PHOX2B mutation) and Hirschsprung’s disease and later found a further mutation of BRAF oncogene. This describes a novel association between these mutations and the shared qualities of tumorigenesis between BRAF and PHOX2B.
Introduction
Haddad syndrome was first reported by Haddad in 1978 as a simultaneous combination of Congenital Central Hypoventilation Syndrome (CCHS) and Hirschsprung’s disease [1]. The paired-like homeobox gene PHOX2B is the disease-defining gene for CCHS and, therefore, a mutation in the PHOX2B gene is requisite to the diagnosis of CCHS [2].
The RAF kinase family consists of A-RAF, B-RAF, and C-RAF (RAF-1). It has been intensively studied as activators of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) module in regulated and deregulated proliferation. Evidence has accumulated that B-RAF is the main mitogen-activated protein kinase [3].
Case report
A male infant was born at 36 weeks gestation following a normal pregnancy, a spontaneous onset of labor and normal delivery to non-consanguineous East African parents. Birth weight was 3180 g. His mother was 33 year-old and had a history of previously treated Treponema pallidum infection (TPPA positive 1 : 320 and RPR negative).
He cried immediately after birth but, at 12 minutes of age, there were concerns about shallow respiration and low oxygen saturations around 50% in room air. There was no bradycardia. He was intubated, ventilated and transferred to the neonatal intensive care unit. He was commenced on intravenous antibiotics (benzylpencillin and gentamicin) for suspected sepsis.
Within few days of life, he developed abdominal distension associated with difficulty opening his bowels. This responded to twice daily rectal washouts. A contrast study showed a dilated colon with reduced motility. Rectal suction biopsies showed no ganglion cells and hypertrophied nerves were present in the submucosa. In addition, immunohistochemistry for Calretinin was negative confirming the diagnosis of Hirschsprung’s disease.
Over the first few weeks of life, he required continuous ventilator support and had multiple failed extubations. Following extubation, a pattern emerged of hypoventilation and apnea associated with sleep. This characteristic finding resulted in the diagnosis of CCHS which was confirmed by gene mutation (PHOX2B).
Around three month of age, a further gene mutation (BRAF) was identified. Given this additional diagnosis and after careful extensive discussion with his parents, a decision was made to re-orientate his care.
Discussion
CCHS is a rare life-threatening disorder characterized by hypoventilation during sleep and is combined with relatively less severe impairments of autonomic functions including thermoregulation, cardiac rhythm, and digestive motility [4].
Analyzing for the length of the poly-alanine tract in exon 3 of the PHOX2B gene, this patient had a normal allele (20-residue poly-alanine tract) and an expansion mutation. Sequence analysis of the poly-alanine tract was undertaken; this confirmed the presence of the expansion mutation and sized it as a 7 alanine expansion.
Whenever the mutation does not result in a poly-alanine expansion, PHOX2B found to be a predisposing gene to tumors of sympathetic nervous system such as neuroblastoma [5]. Hirschsprung’s disease is reported in 87 to 100% of non-poly-alanine repeat mutations in contrast to 13 to 20% of Poly-alanine repeat mutations, Fig. 1 [6]. However, phenotypic variability in expression of disease is seen in families with the same mutations in PHOX2B gene [7].
Phenotype variability in polyalcohol and non-polyalanine PHOX2B repeat mutations.
Mutations of B-RAF results in increased cell division, and cell survival [8]. Inhibitors of RAF kinase may harbor therapeutic potential in tumors carrying a BRAF oncogene [9].
The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD, neurofibromatosis type 1, Costello and cardio-facio-cutaneous syndromes [10].
In this baby, microarray studies on DNA extracted from peripheral blood showed a male profile with a copy number imbalance noted outside regions of known polymorphic regions in the general population. This DNA gain lies within 7q34 and is between 0.44 mb and 0. 56 mb in size. This has been confirmed using a second microarray platform. This region contains five protein-coding genes and disrupts the one OMIM Morbid gene BRAF.
Usually patients with a BRAF mutation have significant cognitive impairment. Although, a patient with LEOPARD syndrome and normal intelligence was reported to carry a novel sequence (p.L245F) change in BRAF [11].
Interestingly, B-RAF was found essential for vascular development in the placenta. BRAF-deficient placenta showed complete absence of phosphorylated ERK and strongly reduced hypoxia-inducible factor 1-alpha (HIF-1a) and vascular endothelial growth factor (VEGF) levels [3]. However, this baby had a good weight for his gestational age and there were no signs of placental insufficiency antenatally or postnatally.
Conflict of interest
None to declare.
Footnotes
Acknowledgments
I thank Dr Shore, Dr Chetcuti, and neonatal unit team at Leeds General Infirmary.