Malouf syndrome

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Malouf syndrome
Other namesDilated cardiomyopathy-hypergonadotropic hypogonadism syndrome

Najjar syndrome

Cardiogenital syndrome

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). [1]

Contents

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. [2] The study consisted of two sisters that presented with hypergonadotropic hypogonadism, dilated cardiomyopathy, blepharoptosis, and a broad nasal base. [3] 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. [4] In 1992, a new case study of an 18-year-old female conducted by Narahara et al. resulted in similar findings as Malouf. [5] Although the prevalence of Malouf syndrome is unknown, there are less than 20 affected families discussed in literature. [6] While there is no specific cure for Malouf syndrome, symptoms can be treated. [7] 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. [4] It is characterized by a combination of features that can affect the skeletal, cardiovascular, and skin systems.

Symptoms: [6]

Note: it is possible that males with Malouf syndrome display cardiomyopathy but not testicular dysgenesis [23]

Genetics

Malouf syndrome involves an autosomal recessive inheritance pattern in that it is a recessive trait that is inherited. [23] It is caused by a heterozygous missense mutation in the LMNA gene located on chromosome 1 (1q22). [23] 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. [24] [25] 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. [26] 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, [26] therefore making it harder to distinguish whether a patient is displaying signs of Malouf syndrome or some other disease.[ citation needed ] 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 substitued 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. [24]

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. [1]

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. [27] Dr. Malouf noted that this disease is familial - and therefore congenital - as the two sisters were children of first degree cousins. [28]

In 1992, Kouji Narahara examined an 18-year-old girl who displayed the same symptoms seen by Dr. Malouf in his patients. [27] 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. [29]

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.[ citation needed ]

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.[ citation needed ]

Management

Due to the rare nature of the disease, it has been difficult to understand any underlying mechanisms that cause Malouf syndrome. At its current state, there are no specific treatment regimens or therapies to specifically address Malouf syndrome. However, there are ways to manage the symptoms associated with the disease and other lamin-associated dilated cardiomyopathies. [30] [31] Specifically, with respect to Lamin A/C (LMNA) cardiomyopathy, the current treatment follows the standard heart failure regimen. [32] As noted by Dr. Zhang et al., the treatment for standard heart failures in relation to LMNA cardiomyopathy uses "beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and aldosterone antagonists, but the specific efficacy in this population is undetermined." [32] Depending on the patient's case, treatment may need a variety of medications to address the symptoms. [33]

Drugs: [33] used to treat dilated cardiomyopathy.

Angiotensin-converting enzyme (ACE) inhibitors- This type of medicine enlarges blood vessels and lowers blood pressure in order to improve an individual's blood flow. Some of the side effects are dry cough, low blood pressure, low white blood cell count, and kidney or liver problems. [34] Examples: Lisinopril (Zestril), Benazepril (Lotensin).

Angiotensin II receptor blockers (ARBs)- ARBs are an alternative blood pressure-lowering medication that can be used if a person cannot tolerate ACE inhibitors. Some of the side effects are hyperkalemia, hypotension, and acute renal failure. [35] Examples: Losartan (Cozaar), Olmesartan (Benicar).

Anticoagulants- This type of drug helps in preventing blood clots but can cause bruising or bleeding. [36] Examples: Rivaroxaban (Xarelto), Apixaban (Eliquis), Warfarin (Coumadin).

Sacubitril/Valsartan (Entresto)- This combination drug includes an ARB and ACE inhibitor to help pump blood from your heart to the rest of your body. This drug is mainly for people with chronic heart failure. Common side effects include cough, hyperkalemia, and angioedema. [37]

Beta-blockers- This class of drug slows your heart rate and lowers blood pressure. This medication may also prevent the harmful effects of stress hormones. Some of the side effects of this medication include dizziness, low blood pressure, fatigue, and reduced exercise tolerance. [38] Examples: Metoprolol (Betaloc or Lopressor), Atenolol (Tenormin).

Diuretics- This type of drug removes excess fluid and salt from the body as well as the lungs, as excess fluid in the body can strain the heart by forcing it to pump harder. Some of the side effects include increased urination and hyperkalemia. [39] Examples: Furosemide (Lasix), Hydrochlorothiazide (Microzide).

Digoxin (Lanoxin)- The purpose of this drug is to strengthen heart muscle contractions and slow down the heartbeat. This drug can reduce heart failure symptoms and improve your ability to be more active. One thing to note is that the use of digoxin requires frequent monitoring due to its narrow therapeutic window. Some of the side effects include rash, headache, hypokalemia, and arrhythmias. [40]

Ivabradine (Corlanor)- This drug restores normal heartbeat by slowing down and regulating the heart rate. It is indicated for the treatment of stable angina pectoris and heart failure with reduced ejection fraction but has seen an increasing role in treating dilated cardiomyopathy due to its improvement of cardiac function. Some side effects of Ivabradine include bradycardia (slow heart rate), atrial fibrillation, and hypertension. [41]

Therapeutic devices: [33] can be surgically implemented to help treat dilated cardiomyopathy.

Biventricular pacemaker- This device sends out electrical signals in order to control contractions between the left and right ventricles. It is used for people who have heart failure and irregular heartbeats.

Implantable cardioverter-defibrillators (ICD)- Although this device does not treat cardiomyopathy itself, it does help prevent arrhythmias, which are commonly caused by cardiomyopathy. Implantable cardioverter-defibrillators monitor the heartbeat and send electrical shocks to control any rapid or abnormal rhythms. This device can also serve as a pacemaker which works similarly to keep the heart beating at a normal rate and rhythm).

Left ventricular assist devices (LVAD)- This device is attached to the heart and either the abdomen or chest in order to help the weakened heart pump blood. It is usually considered after other approaches have proven unsuccessful and can be used as treatment while waiting for a heart transplant.

Hypergonadotropic hypogonadism hormone replacement therapy:

Hormonal replacement therapy (testosterone, estrogen, progesterone, pituitary hormones, et cetera)- This treatment consists of taking medications containing the hormone that the body is lacking to replace the ones that the body no longer produces. These medications can come in the form of pills, patches, gels, or injections. [42] [43]

It is important to note, Malouf syndrome will require regular monitoring. Due to the nature of the disease, and given the potential for progressive symptoms, ongoing monitoring and evaluation by specialists in cardiology, dermatology, and orthopedics are recommended. Genetic counseling may also be beneficial for affected individuals and their families to understand the inheritance pattern and implications.

In summary, Malouf syndrome is a complex disorder requiring a tailored approach to care. As research advances, further understanding of the genetic underpinnings of this condition may lead to more precise diagnostic tools and targeted therapies.

Epidemiology

The prevalence of Malouf syndrome is unknown at the moment and has not been fully defined. About 20 families from around the world, whose members have cardiogential syndrome, have been found in literature. However, the prevalence of familial dilated cardiomyopathy ranges from 30 to 50% cases, with 40% having an identifiable genetic cause. [44] Dilated cardiomyopathy was originally classified as a rare disease, but the possibility of a familiar substrate was ignored. Dilated cardiomyopathy was later found to be a major cause of heart failure, especially among young patients. [44] Dilated cardiomyopathy began to be identified as a systemic condition rather than an isolated disease. [44] Even despite these major efforts and contributions, the incidence and prevalence of dilated cardiomyopathy remain unknown. [44]

See also

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.

Related Research Articles

<span class="mw-page-title-main">Marfan syndrome</span> Genetic disorder involving connective tissue

Marfan syndrome (MFS) is a multi-systemic genetic disorder that affects the connective tissue. Those with the condition tend to be tall and thin, with long arms, legs, fingers, and toes. They also typically have exceptionally flexible joints and abnormally curved spines. The most serious complications involve the heart and aorta, with an increased risk of mitral valve prolapse and aortic aneurysm. The lungs, eyes, bones, and the covering of the spinal cord are also commonly affected. The severity of the symptoms is variable.

<span class="mw-page-title-main">Cardiomyopathy</span> Disease of the heart muscle

Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. An irregular heart beat and fainting may occur. Those affected are at an increased risk of sudden cardiac death.

<span class="mw-page-title-main">Progeria</span> Genetic disorder that causes early aging

Progeria is a specific type of progeroid syndrome, also known as Hutchinson–Gilford syndrome or Hutchinson–Gilford progeroid syndrome (HGPS). A single gene mutation is responsible for causing progeria. The affected gene, known as lamin A (LMNA), makes a protein necessary for holding the cell nucleus together. When this gene gets mutated, an abnormal form of lamin A protein called progerin is produced. Progeroid syndromes are a group of diseases that cause individuals to age faster than usual, leading to them appearing older than they actually are. People born with progeria typically live until their mid- to late-teens or early twenties.

Barth syndrome (BTHS) is a rare but serious X-linked genetic disorder, caused by changes in phospholipid structure and metabolism. It may affect multiple body systems, and is potentially fatal. The syndrome is diagnosed almost exclusively in males.

<span class="mw-page-title-main">Wolfram syndrome</span> Human disease

Wolfram syndrome, also called DIDMOAD, is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders including neurodegeneration. Symptoms can start to appear as early as childhood to adult years. There is a 25% recurrence risk in children.

<span class="mw-page-title-main">Dilated cardiomyopathy</span> Condition involving an enlarged, ineffective heart

Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. Complications can include heart failure, heart valve disease, or an irregular heartbeat.

Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormonal signs that puberty has begun. In the United States, girls are considered to have delayed puberty if they lack breast development by age 13 or have not started menstruating by age 15. Boys are considered to have delayed puberty if they lack enlargement of the testicles by age 14. Delayed puberty affects about 2% of adolescents.

Hypogonadism means diminished functional activity of the gonads—the testicles or the ovaries—that may result in diminished production of sex hormones. Low androgen levels are referred to as hypoandrogenism and low estrogen as hypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.

<span class="mw-page-title-main">Bardet–Biedl syndrome</span> Ciliopathic recessive genetic disorder

Bardet–Biedl syndrome (BBS) is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized by rod/cone dystrophy, polydactyly, central obesity, hypogonadism, and kidney dysfunction in some cases. Historically, slower mental processing has also been considered a principal symptom but is now not regarded as such.

<span class="mw-page-title-main">Cardiomegaly</span> Medical condition

Cardiomegaly is a medical condition in which the heart becomes enlarged. It is more commonly referred to simply as "having an enlarged heart". It is usually the result of underlying conditions that make the heart work harder, such as obesity, heart valve disease, high blood pressure (hypertension), and coronary artery disease. Cardiomyopathy is also associated with cardiomegaly.

<span class="mw-page-title-main">Alström syndrome</span> Rare genetic disorder involving childhood obesity and multiple organ dysfunction

Alström syndrome (AS), also called Alström–Hallgren syndrome, is a very rare autosomal recessive genetic disorder characterised by childhood obesity and multiple organ dysfunction. Symptoms include early-onset type 2 diabetes, cone-rod dystrophy resulting in blindness, sensorineural hearing loss and dilated cardiomyopathy. Endocrine disorders typically also occur, such as hypergonadotrophic hypogonadism and hypothyroidism, as well as acanthosis nigricans resulting from hyperinsulinemia. Developmental delay is seen in almost half of people with Alström syndrome.

<span class="mw-page-title-main">Endocrine disease</span> Disorders of the endocrine system

Endocrine diseases are disorders of the endocrine system. The branch of medicine associated with endocrine disorders is known as endocrinology.

<span class="mw-page-title-main">Laminopathy</span> Medical condition

Laminopathies are a group of rare genetic disorders caused by mutations in genes encoding proteins of the nuclear lamina. Since the first reports of laminopathies in the late 1990s, increased research efforts have started to uncover the vital role of nuclear envelope proteins in cell and tissue integrity in animals. Laminopathies are a group of degenerative diseases, other disorders associated with inner nuclear membrane proteins are known as nuclear envelopathies.

<span class="mw-page-title-main">Prelamin-A/C</span> Filament protein

Prelamin-A/C, or lamin A/C is a protein that in humans is encoded by the LMNA gene. Lamin A/C belongs to the lamin family of proteins.

<span class="mw-page-title-main">Alcoholic cardiomyopathy</span> Medical condition

Alcoholic cardiomyopathy (ACM) is a disease in which the long-term consumption of alcohol leads to heart failure. ACM is a type of dilated cardiomyopathy. The heart is unable to pump blood efficiently, leading to heart failure. It can affect other parts of the body if the heart failure is severe. It is most common in males between the ages of 35 and 50.

<span class="mw-page-title-main">Renal–hepatic–pancreatic dysplasia</span> Medical condition

Renal–hepatic–pancreatic dysplasia is an autosomal recessive congenital disorder characterized by pancreatic fibrosis, renal dysplasia and hepatic dysgenesis. An association with NPHP3 has been described. It was characterized in 1959.

Danon disease is a metabolic disorder. Danon disease is an X-linked lysosomal and glycogen storage disorder associated with hypertrophic cardiomyopathy, skeletal muscle weakness, and intellectual disability. It is inherited in an X-linked dominant pattern.

<span class="mw-page-title-main">Rud syndrome</span> Medical condition

Rud syndrome is a poorly characterized disorder, probably of X-linked recessive inheritance, named after Einar Rud who described 2 patients with the case in 1927 and 1929. It was argued that all reported cases of Rud syndrome are genetically heterogeneous and significantly differ from the original case reports of Rud and that the designation Rud syndrome should be eliminated and that the patients with such diagnosis should be reassigned to other syndromes, such as Refsum disease and Sjögren-Larsson syndrome. Some consider Rud syndrome and Sjögren-Larsson syndrome the same entity and that Rud syndrome does not exist.

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.

<span class="mw-page-title-main">Heart-hand syndrome, Slovenian type</span> Medical condition

Heart-hand syndrome, Slovenian type is a rare autosomal dominant genetic disorder belonging to the heart-hand syndromes.

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