Malpuech facial clefting syndrome

Overview

Malpuech facial clefting syndrome, also known as Malpuech syndrome, is a rare genetic disorder characterized by a combination of distinctive facial abnormalities, developmental delays, and genitourinary and skeletal anomalies. It belongs to a group of related conditions sometimes referred to as the 3MC syndromes, which include Malpuech, Michels, Mingarelli, and Carnevale syndromes. These syndromes are now understood to be part of a single clinical spectrum caused by mutations in genes related to cellular migration during early development.

First described by Malpuech and colleagues in 1983, the syndrome is notable for features such as facial clefts, hypertelorism (wide-set eyes), craniosynostosis, and genital anomalies. The condition affects both males and females and typically presents at birth or in early infancy. Because of its wide range of symptoms and varying severity, diagnosis and management require a multidisciplinary approach.

Causes

Malpuech syndrome is caused by mutations in genes that are involved in the regulation of cell migration and tissue development. The most commonly associated genes include:

• COLEC11

• MASP1

Both of these genes are involved in the lectin complement pathway, which plays a role in immune system function and embryonic development. Mutations in these genes disrupt normal craniofacial, skeletal, and organ formation.

The condition is inherited in an autosomal recessive pattern, meaning a child must inherit one copy of the mutated gene from each parent to develop the syndrome. Parents who each carry one copy of the mutated gene are typically asymptomatic but have a 25% chance with each pregnancy of having an affected child.

Symptoms

The symptoms of Malpuech facial clefting syndrome can vary widely but commonly include:

• Facial anomalies:

  • Cleft lip and/or cleft palate

  • Hypertelorism (abnormally wide-spaced eyes)

  • Flat nasal bridge

  • Micrognathia (small lower jaw)

• Genitourinary anomalies:

  • Ambiguous genitalia

  • Hypospadias (in males)

  • Renal malformations or hypoplasia

• Skeletal abnormalities:

  • Short stature

  • Joint contractures

  • Spinal anomalies in some cases

• Neurological and developmental issues:

  • Global developmental delay

  • Intellectual disability (mild to moderate)

  • Hearing loss (often due to ear malformations)

• Other findings:

  • Craniosynostosis (premature fusion of skull bones)

  • Umbilical hernia

  • Hypotonia (reduced muscle tone)

Because of the overlapping features with other 3MC syndromes, clinical presentation alone may not be sufficient for definitive diagnosis.

Diagnosis

Diagnosis of Malpuech syndrome is based on clinical features, family history, and confirmatory genetic testing. Key diagnostic steps include:

• Physical examination: Identification of characteristic facial, skeletal, and genitourinary anomalies.

• Medical imaging:

  • CT or MRI of the skull to evaluate craniosynostosis

  • Ultrasound or MRI of the kidneys and reproductive organs

• Developmental assessment: Evaluation of motor, cognitive, and language skills.

• Audiological testing: To assess for conductive or sensorineural hearing loss.

• Genetic testing:

  • Targeted sequencing or panel testing for mutations in COLEC11 and MASP1

  • Whole-exome sequencing may be considered in atypical or unclear cases

Prenatal diagnosis is possible through chorionic villus sampling or amniocentesis if a known familial mutation is identified.

Treatment

There is no cure for Malpuech syndrome. Treatment is supportive and symptom-based, requiring a coordinated, multidisciplinary approach. Common management strategies include:

• Surgical correction:

  • Repair of cleft lip and/or palate

  • Urological surgeries for genitourinary abnormalities

  • Surgical intervention for craniosynostosis if present

• Developmental therapies:

  • Speech therapy for communication and feeding difficulties

  • Occupational and physical therapy for motor delays and hypotonia

• Hearing support:

  • Hearing aids or surgical interventions as needed

  • Frequent hearing evaluations

• Medical monitoring:

  • Regular follow-up for renal function and growth

  • Endocrine evaluations in case of pubertal or hormonal concerns

• Genetic counseling: For affected families, especially where consanguinity is a factor.

Early intervention services can greatly improve developmental outcomes and quality of life for affected children.

Prognosis

The prognosis of Malpuech facial clefting syndrome varies depending on the severity and combination of anomalies present. Most individuals will experience developmental delays, but with supportive care and therapy, many can achieve significant developmental milestones. Hearing and speech issues may persist but can be managed with early intervention.

Lifespan is generally not severely affected unless there are serious complications involving the kidneys, heart, or central nervous system. Regular monitoring, surgical management of physical anomalies, and supportive therapies can significantly improve the quality of life.

As awareness of the 3MC spectrum syndromes grows and genetic testing becomes more accessible, earlier diagnosis and better-targeted treatments may help improve outcomes for individuals with Malpuech syndrome.