Rare Case of Pulmonary Hypertension in Genetic Disease Exposes Limited Knowledge of PH Mechanisms

Pulmonary hypertension (PH) only rarely affects children born with the genetic condition incontinentia pigmenti, illustrating that researchers lack insights into how molecular abnormalities translate into problems in the heart and lungs.

A case report by researchers from Saudi Arabia’s King Abdullah International Medical Research Center in Riyadh illustrates the condition, and attempts to explain why doctors only rarely see lung hypertension in these patients. Their study, “Pulmonary hypertension and vasculopathy in incontinentia pigmenti: a case report,” appeared in the journal Therapeutics and Clinical Risk Management.

Incontinentia pigmenti is caused by mutations in the IKBKG gene, which codes for a factor involved in activating a molecule called NF-κB — most known for its role in the immune system.

Although NF-κB is a crucial immune molecule in adults, it also promotes the development of bone, mammary glands, skin, and central nervous system tissue in the growing fetus. Babies born with the condition typically have skin lesions and a range of other abnormalities including eye and brain damage.

The IKBKG gene sits on the X-chromosome, and one mutated chromosome is enough for the disease to develop. Because men only have one X-chromosome, boys with the condition usually die before birth, meaning the disease affects mostly girls.

The report describes a girl — born to unrelated parents — who showed symptoms soon after birth. Breathing difficulties brought her to the Saudi hospital’s neonatal intensive care unit, where she was put on mechanical ventilation. Examinations indicated pulmonary hypertension. The baby developed a skin rash, which doctors first suspected was a herpes simplex or impetigo infection. The authors noted that about 90 percent of all children born with the disease are first suspected of having one of the two infections.

Over time, the lesions became intensely pigmented  — a typical development of the disease. Eventually, doctors sent the girl sent home, but her lung hypertension persisted. She had episodes of blue spells, or cyanotic spells. At 18 months, her persistent PH was treated with the diuretic furosemide (sold as Furocot or Lasix). At the age of two, doctors added Revatio (sildenafil) to her treatment.

The hyperpigmented skin lesions remained, and the girl also developed lesions that lacked pigmentation. Unlike most children with the disease, she did not have any neurological abnormalities. Yet a more extensive heart examination showed she had several abnormalities in her heart and lungs. Catheterization revealed she had a deformed heart and narrowed lung arteries, which in some places were completely obstructed.

Gene tests revealed that she had a typical mutation in the IKBKG gene.

Scientific literature has described only five previous cases of incontinentia pigmenti with lung hypertension. In contrast to the other children — who died early — the girl in the current report responded well to treatment and was still alive at three years of age. Her lack of brain and eye damage also made her stand out from the other cases.

While little is known about how the gene mutation can cause PH, the research team attempted to explain these differences with the concept of lionization — a process in which all X-chromosomes but one,become inactivated in cells. So if the mutated X-chromosome in the girl’s brain was inactivated, it left her with one functioning chromosome in these cells.

Disease symptoms were only seen in the cells where the faulty X-chromosome remained active. While an earlier study proposed this idea, no current evidence exists to suggest that the mechanism determines the type of symptoms developed by children with incontinentia pigmenti.