Malouf syndrome (also known as "congestive cardiomyopathy-hypergonadotropic hypogonadism syndrome") is a congenital disorder that causes one or more of the following symptoms: intellectual disability, ovarian dysgenesis, congestive cardiomyopathy, broad nasal base, blepharoptosis, and bone abnormalities, and occasionally marfanoid habitus (tall stature with long and thin limbs, little subcutaneous fat, arachnodactyly, joint hyperextension, narrow face, small chin, large testes, and hypotonia).
This congenital disease was first classified in 1985 by Dr. Joe Malouf, who performed a case study on two sisters that displayed this rare syndrome. The study consisted of two sisters that presented with hypergonadotropic hypogonadism, dilated cardiomyopathy, blepharoptosis, and a broad nasal base. Upon further analysis of their genetic lineage, it was found that the parents of the sisters were first-degree cousins; Malouf then classified the syndrome as a familial disorder. In 1992, a new case study of an 18-year-old female conducted by Narahara et al. resulted in similar findings as Malouf. Although the prevalence of Malouf syndrome is unknown, there are less than 20 affected families discussed in literature. While there is no specific cure for Malouf syndrome, symptoms can be treated. The treatment options are individualized and should be determined by a doctor or specialist.
Signs and symptoms
The main symptoms of this disease are hypergonadotropic hypogonadism and cardiomyopathy, whose coexistence is extremely rare. It is characterized by a combination of features that can affect the skeletal, cardiovascular, and skin systems.
Symptoms: Hypergonadotropic hypogonadism: impaired testicular function. Hypergonadotropic hypogonadism can be acquired or can be present from birth. Cardiomyopathy: muscle or electrical dysfunction of the heart which often leads to progressive heart failure. There are many different types of cardiomyopathies. Cardiomyopathies are usually asymptomatic in the early stages, but can have similar symptoms to heart failure such as shortness of breath, fatigue, cough, orthopnea, dyspnea, and edema. Treatment is based on the patients symptoms and on whether it is obstructive or nonobstructive. There are many different approaches to treatment strategies for cardiomyopathies. Dilated cardiomyopathy: identified by presence of left ventricular dilation and contractile dysfunction. Genetic mutations such as Malouf syndrome account for 35% of the cases of dilated cardiomyopathy. Symptoms of dilated cardiomyopathy are similar to congestive heart failure. Blepharoptosis: a common eyelid disorder which causes an abnormally low or drooping of one or both upper eyelids. Symptoms of blepharoptosis range from an asymptomatic cosmetic effect to significant visual deficits. There are several different classifications of blepharoptosis. Broad nasal base: while this may be perfectly normal in certain individuals, it can also be a symptom of a congenital disorder Marfanoid habitus: a congenital syndrome that is physically characterized by long limbs and a flat face that may resemble Marfan syndrome along with learning and motor disabilities Metabolic abnormalities Thyroid hemiagenisis: a rare congenital abnormality of the thyroid gland characterized by the absence of one lobe Aged appearance of the feet Diabetes mellitus: chronic metabolic disorder reducing the ability for and individual to regulate the level of glucose in their blood stream. There are several classifications of diabetes mellitus. These classifications include type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the young, gestational diabetes, neonatal diabetes, and steroid-induced diabetes. The initial treatment to diabetes mellitus is through lifestyle modifications through physical activity and diet changes. When these non-pharmacologic approaches do not result in normalization of the metabolic abnormalities, there are several different pharmacologic therapies that are available. Collagenoma: rare collections of malformed cells that are densely composed of collagen This is usually treated by resection or electrical cauterizations, but it varies from patient to patient. Ovarian dysgenesis (female): females with ovarian dysgenesis do not have germ cells. They do however have the female phenotype, but they lack sexual characteristics. Hypoplastic genitalia: underdeveloped genitalia Undescended testis (males): also known as cryptorchidism. Undescended testis is a condition in which the testicles fail to descend into the scrotum. It is a common birth defect and surgical treatment is the recommended option. For children, the surgery is an orchiopexy. For adults with undescended testis, the treatment approach is an orchiectomy in which one or both testicles are surgically removed. If left untreated, fertility disorders may occur. Micropenis (males): clinically diagnosed as 2.5 standard deviations of the mean in a patient with normal internal and external male genitalia. Small testis (males): clinically defined as testes that are smaller than the 50th percentile for age.
Note: it is possible that males with Malouf syndrome display cardiomyopathy but not testicular dysgenesis
Genetics Malouf syndrome involves an autosomal recessive inheritance pattern in that it is a recessive trait that is inherited. It is caused by a heterozygous missense mutation in the LMNA gene located on chromosome 1 (1q22). The person inherits two copies of this mutation from both of the parents - meaning both parents are carriers of this mutation - leading to the development of the syndrome. The LMNA gene encodes for lamin A and lamin C which are important proteins produced by almost every type of cell in the body. The lamin family of proteins are components of the nuclear lamina that consists of a protein network within the inner nuclear membrane that determine nuclear stability, chromatin structure and gene expression. Mutations in this gene can lead to several diseases besides Malouf syndrome, such as familial partial lipodystrophy, limb girdle muscular dystrophy, and Hutchinson-Gilford progeria syndrome, therefore making it harder to distinguish whether a patient is displaying signs of Malouf syndrome or some other disease. The LMNA mutation can show up in many different tissues including cardiac, skeletal, nervous, adipose, and cutaneous tissue.
The most common heterozygous mutations found in the LMNA gene are a heterozygous de novo ala57-to-pro substitution (A57P), which means the Alanine amino acid at position 57 was substituted by a Proline, resulting from a 584G-C transversion in the LMNA gene and a de novo 176T-C transition in exon 1 leading to a leu59-to-arg (L59R) substitution.
Further genetic research and advanced molecular techniques are necessary to identify the specific genetic defects and pathways involved in Malouf syndrome. The genetic basis of Malouf syndrome remains incompletely understood, contributing to challenges in diagnosis and management.
Diagnosis There is no set criteria used to diagnose Malouf syndrome. Signs and symptoms such as congestive or dilated cardiomyopathy, ovarian dysgenesis in females or primary testicular failure in males, intellectual disability, broad nasal base, blepharoptosis, skin lesions, and skeletal abnormalities are used as a reference to diagnosis this rare disease, and genetic testing of the LMNA gene can serve as a way to confirm a diagnosis.
Malouf syndrome was first diagnosed in 1985 by Dr. Joe Malouf. Dr. Malouf examined two sisters who exhibited congestive cardiomyopathy associated with ovarian dysgenesis, secondary hypergonadotropic hypogonadism, bilateral ptosis, and prominent nasal bones. Dr. Malouf noted that this disease is familial - and therefore congenital - as the two sisters were children of first degree cousins.
In 1992, Kouji Narahara examined an 18-year-old girl who displayed the same symptoms seen by Dr. Malouf in his patients. She was described as having delayed intellectual development, mild cardiomegaly, broad nasal base and several signs of Marfan syndrome such as small stature, arachnodactyly, and a large arm span. With further testing, it was found that she had several electrocardiography (ECG) deviations which were concluded to be left-side dilated cardiomyopathy and congestive heart failure. In addition to cardiomyopathy, many of her reproductive organs were also significantly impacted such as hypoplasia of her uterus, vagina, and fallopian tubes. Dr. Narahara was able to conclude that the girl had Malouf syndrome because it is extremely rare to see gonadal dysgenesis and cardiomyopathy in the same patient, which both his patient and Dr. Malouf's patients exhibited.
Diagnosis of this syndrome is sometimes conflicting as the symptoms displayed match those of other diseases such as limb girdle muscular dystrophy, Hutchinson-Gilford progeria syndrome, Noonan syndrome et cetera. As a result, it has been often questioned as to whether Malouf syndrome truly is a new syndrome that should be accepted.
In particular, Noonan syndrome has been the most significant condition that is considered in the differential diagnosis of Malouf syndrome because of the similarity in its signs and clinical manifestations to those of Malouf syndrome. However, certain fundamental signs and symptoms that are unique only to Malouf syndrome were able to be the distinguishing factor in diagnosis. Some of these signs and symptoms include small stature, abnormalities of the thorax, and a webbed neck.
Despite all of this, providers are strongly encouraged to keep Malouf syndrome in mind with the differential diagnosis of dilated cardiomyopathy until further evidence is discovered which will lead to a more guided approach to diagnosing patients. Differential diagnosis Due to the clinically overlapping characteristics, distinguishing Malouf syndrome from other diseases can be challenging. For instance, Malouf syndrome shares similarities with Marfan syndrome, such as a tall and slender build, long limbs, and mitral valve prolapse, making it difficult to differentiate between the two based solely on physical examination. Additionally, other connective tissue disorders like Ehlers-Danlos syndrome, Loeys-Dietz syndrome, and homocystinuria can present with overlapping features such as hypermobility, skin laxity, and cardiovascular anomalies. Therefore, a thorough clinical evaluation, including detailed medical history and, where possible, genetic testing, is crucial for an accurate diagnosis and appropriate management. Ehlers-Danlos syndrome: The Ehlers–Danlos syndromes (EDS) are a diverse group of genetic connective tissue disorders impacting collagen production and function, characterized by symptoms such as joint hypermobility, tissue fragility, and severe cardiovascular issues like arterial aneurysms and organ rupture. The updated classification now recognizes 13 subtypes, including hypermobile EDS (hEDS), which is distinguished from hypermobility spectrum disorders (HSD) and has a higher risk of systemic complications. While serious cardiovascular problems are common in some EDS types, hEDS typically features only mild, nonprogressive thoracic aortic dilatation and mitral valve prolapse. Loeys–Dietz syndrome: Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder with systemic involvement, including craniofacial, skeletal, cutaneous, and vascular abnormalities such as arterial tortuosity and aneurysms. The full clinical spectrum of LDS is not yet fully understood due to limited large-scale studies. The prevalence of LDS is also unknown, with current knowledge based on small cohorts and case reports.