holoprosencephaly-radial heart renal anomalies syndrome

Holoprosencephaly-radial heart renal anomalies syndrome is an extremely rare, multisystem congenital condition that primarily affects formation of the brain, limbs, heart, and kidneys before birth. Fewer than one in a million people are thought to be affected, and most cases are identified in the newborn period because of striking structural differences. The disorder combines severe brain malformation called holoprosencephaly with abnormalities of the upper limbs, congenital heart defects, renal maldevelopment, and absence of the gallbladder. Although it is classified as autosomal dominant, the specific genetic change responsible has not yet been pinpointed, and both isolated cases and familial transmission have been reported.

The clinical picture is dominated by holoprosencephaly, a developmental defect in which the forebrain fails to divide properly. Most affected infants also have microcephaly and characteristic midline facial differences such as absence of the nose, narrow or absent external ear canals, and small or closely spaced eyes. Early presentation often includes feeding difficulties and breathing problems related to these craniofacial changes. Limb findings are another key feature. Many individuals are born without thumbs or with markedly shortened or fused bones of the forearm, and some have more severe reductions such as phocomelia. The ulna and radius may be undersized, and in occasional cases extra toes or foot polydactyly are present. Heart involvement can range from small septal defects to complex malformations such as tetralogy of Fallot or an overriding aorta, which may require early surgical attention. Kidney anomalies include small or absent kidneys or ectopic positioning; about one-third of affected infants also lack a gallbladder. Additional, less common findings include vertebral segmentation defects, missing ribs, neuronal migration abnormalities visible on brain imaging, hearing impairment linked to ear canal atresia, and ocular findings such as iris coloboma or even cyclopia in the most severe presentations. Not all individuals experience all features, and severity can vary considerably even within the same family.

Holoprosencephaly-radial heart renal anomalies syndrome is currently considered autosomal dominant, meaning one altered copy of the responsible gene would be sufficient to cause the condition. However, the precise genetic basis is still under investigation, and no single gene has been definitively linked so far. In families where the syndrome has been observed across generations, each child of an affected individual has a 50 percent chance of inheriting the condition. When a child is the first affected family member, the change may have arisen for the first time in that child, but future transmission to their own children would still follow autosomal dominant expectations. Because clinical expression ranges from mild to very severe, variable expressivity is strongly suspected. Genetic counseling is recommended for parents of an affected child and for any adult who has the diagnosis and is planning a family.

At present, management focuses on supportive and surgical care tailored to each individual’s organ involvement. Newborns often require stabilization of breathing and feeding, sometimes using feeding tubes or airway support. Congenital heart defects, if significant, are managed according to standard pediatric cardiology guidelines and may involve medication or corrective surgery. Limb differences are addressed through orthopedic evaluation, possible reconstructive surgery, and early occupational therapy to maximize hand and arm function. Renal anomalies necessitate monitoring of kidney function and, in severe cases, nephrology input for dialysis or transplantation planning. Hearing impairment is assessed early so that hearing aids or other interventions can support language development. Ongoing care is coordinated by a multidisciplinary team that may include genetics, neurology, cardiology, nephrology, orthopedics, otolaryngology, and developmental specialists. Families benefit from early intervention services and accessible supportive therapies. Patients should discuss available options and surveillance schedules with their healthcare team and pursue genetic counseling for individualized risk assessment.

Outcomes vary widely and depend on the severity of brain malformation, the complexity of cardiac and renal defects, and the success of early medical or surgical interventions. Some infants with severe holoprosencephaly and major organ involvement may have limited survival, whereas others with milder forms can live into childhood or adulthood with appropriate support. Advances in neonatal intensive care, cardiac surgery, and renal replacement therapies have improved survival and quality of life for some affected individuals. Long-term needs often include ongoing medical care, rehabilitation services, and educational support.