Overview

Carpenter syndrome, also known as acrocephalopolysyndactyly (ak-roh-sef-uh-loh-pol-ee-sin-dak-tuh-lee) type 2 or ACPS II, is a rare genetic condition that is caused by mutations to the RAB23 or MEGF8 genes.¹ These genes play a vital role in how cells in the body replicate, grow and die. The gene mutation can be passed down from parents to their children, but it often occurs spontaneously (sporadic mutation). When it is passed down, it is through an autosomal recessive manner, which describes how offspring must inherit the mutated gene from both parents to inherit the syndrome.  The mutations to these genes appear as distinctive skull and limb abnormalities. The condition commonly leads to a cloverleaf skull shape; this is due to the abnormal growth and fusion of skull bones (craniosynostosis) before birth. Other features are fingers and toes joined or webbed (syndactyly) or duplicated (polydactyly). 

Additionally, the existence of cardiac (heart) and other internal organ abnormalities is one of the syndrome's most significant and potentially fatal features. All these internal abnormalities have a prominent effect on a person’s overall health and life expectancy, as the heart, gastrointestinal system, and genitourinary system (also known as the urinary and reproductive system) are vital in key biological processes. 

Cardiac malformations in carpenter syndrome

Congenital (conditions present at birth) cardiac malformations are frequent in people with Carpenter syndrome. The RAB23 and MEGF8 genes send signals that help in the growth of the heart, specifically, they help in guiding the growth of the main heart vessels and the separation of the heart chambers.^2,3 Mutations can affect the structure of the heart, causing improper connections or partitioning.

There is a range of heart malformations that have been seen in people with Carpenter syndrome, including:¹

• Atrial Septal Defect (ASD): 

The formation of a hole or opening between the upper two chambers of the heart (atria)

• Dextrocardia: 

A rare congenital condition where the heart is positioned on the right side of the chest instead of the left

• Patent Ductus Arteriosus (PDA): 

A blood vessel found in babies that normally closes soon after birth remains open, allowing abnormal blood flow

• Pulmonary stenosis: 

Narrowing of the pulmonary valve, which connects blood from the right ventricle to the lungs 

• Tetralogy of Fallot: 

The presence of a combination of four defects: ventricular septal defect, pulmonary stenosis, an overriding aorta, and right ventricular hypertrophy (right ventricle of heart muscle thickens)

• Transposition of the great arteries (TGA): 

Two main arteries leaving the heart, the aorta and pulmonary artery, are switched 

• Ventricular Septal Defect (VSD): 

The formation of a hole or opening between the lower two chambers (ventricles)

Signs and symptoms

As cardiac defects are typically not visible to the naked eye, it is important to recognise their signs and symptoms. These can vary depending on the size and type of the defect:

• Small ASDs or VSDs usually cause no noticeable problems and can close naturally over time
• Larger defects, like Tetralogy of Fallot or TGA, may lead to
  
  • Cyanosis: Bluish lips, nails and skin from low oxygen levels within the blood
  • Fainting, Fatigue and Fussiness
  • Heart murmurs that are detected during examination
  • Poor weight gain or growth
  • Rapid breathing and fatigue: Observed during feeding or on movement in infants

If the heart conditions associated with Carpenter syndrome are not addressed, they can lead to severe and occasionally fatal consequences:

• Heart failure occurs when the heart is unable to pump blood throughout the body as effectively as it should. Fatigue, breathing difficulties, and swelling of the legs or abdomen may result as the heart starts to fail. This is inevitably fatal  if unaddressed
• Pulmonary hypertension, or elevated blood pressure in the arteries found in the lungs, is another consequence. This occurs when the lungs are gradually strained by increased heart pressure or blood flow. As the heart compensates by working harder, it can lead to exhaustion, chest pain, and shortness of breath
• In the most severe cases, untreated defects can lead to life-threatening hypoxia, which means the body is not able to get enough oxygen. This can make the skin and lips turn blue, affect organ function, and, if it goes on for too long, it can be fatal

Other organ malformations

Whilst heart abnormalities are the more common malformation following skull and bone abnormalities, other organ defects can also be a part of Carpenter syndrome. The severity of these can vary, and immediate intervention could be necessary.

Gastrointestinal system malformations in carpenter syndrome

• Abnormal positioning of the liver: 

Research has identified that a child with Carpenter syndrome had a liver that was found in the centre of the body; the liver is usually found in the right side of the body  (those with Carpenter syndrome are known to have their organs positioned differently than usual within the chest or abdomen).⁴

• Malrotation of the intestines:

The intestines do not form properly before the baby is born, which increases the risk of twists in the intestines. The twisting of the intestines can cause the blood supply to the intestines to be blocked, and the tissue in that portion that is blocked can die. ⁵

• Omphalocele:

This is where part of the intestine or liver comes out through the abdominal wall through the umbilical cord, enclosed in a thin sac

• Umbilical hernia: 

Weaker abdominal wall muscles allow a bulge to be formed at the belly button

Digestion and nutrient absorption can be affected due to gastrointestinal abnormalities such as malrotation or omphalocele. In severe cases, these conditions can become medical emergencies that require urgent intervention by healthcare professionals to prevent potentially life-threatening complications.

Genitourinary system malformations in carpenter syndrome

The genitourinary system includes both the urinary and reproductive organs, both of which are affected in Carpenter syndrome. This includes vital organs such as the bladder, kidney, female and male genitalia.

Kidney abnormalities

• Chronic kidney disease (CKD):

Some people with Carpenter syndrome may develop this chronic illness in which the kidneys gradually lose their ability to filter waste and excess fluid from the blood. Research suggests that problems with the way the urinary system is formed may be the cause of this. High blood pressure, changes in urine, weariness, and facial or limb swelling are symptoms related to CKD. Treatments that can delay progression and preserve kidney function include blood pressure management, dietary changes and dialysis ⁶

• Abnormal positioning of the kidney: 

As noted before, research also shows that incorrect positioning of the kidneys in some people with Carpenter syndrome is also seen with other organs, like the heart or liver 

• Hydronephrosis: 

This is when one or both kidneys become bigger because there is a buildup of urine, typically as a result of the urinary system becoming narrowed or blocked. It may happen alongside with other abnormalities of the urinary system in Carpenter syndrome. Back or side pain, fever, nausea, and altered urine are some of the symptoms. Hydronephrosis can cause infections and irreversible kidney damage if treatment is not received. Depending on the cause, treatment options depend on the healthcare professional's judgement but include drainage with a catheter or surgery.¹

Reproductive organ abnormalities

• External genital hypoplasia:

This is the underdevelopment of the external reproductive organs. In people assigned male at birth, this includes the penis, scrotum or testes.¹ Whereas, in people assigned female at birth, this is the bartholin’s gland, clitoris, labia minora, labia majora and mons pubis.

• Undescended testes (cryptorchidism)

This is the absence of at least one testis or both testes from the scrotum.¹ 

Summary

Although Carpenter syndrome is a rare genetic illness characterised by unique deformities of the skull and limbs, its internal complications, particularly those related to the heart and organs, have a significant impact on the general health and prognosis of those who are affected. 

Small septal defects to more severe abnormalities like Tetralogy of Fallot are among the heart anomalies reported in Carpenter syndrome. In addition to the heart, other organs within the genitourinary and gastrointestinal systems are usually affected in this syndrome. 

Whereas gastrointestinal defects like omphalocele, malrotation, and ectopic organs can complicate function and digestion, surgical intervention is normally necessary to repair the defect. Genital and urinary disorders like hydronephrosis, chronic kidney disease, undescended testes, and external genitalia hypoplasia are also associated with Carpenter syndrome.

Early diagnosis, intervention, and awareness are important since they play a crucial role in a person’s health. Through screening, either before birth or after, parents and healthcare professionals will be able to get a clearer idea of the malformations present within the person. Despite all these various associated complicated issues, many people with Carpenter syndrome can enjoy improved health with regular check-ups and coordinated care from their healthcare team.