NORD gratefully acknowledges Leena Tran, MS, Sabina Cook, MS, and Jennefer Kohler, MS, CGC, from the Stanford University MS Program in Human Genetics and Genetic Counseling for assistance in the preparation of this report.
Melnick-Needles syndrome (MNS) is a rare genetic disorder of bone characterized by skeletal and craniofacial abnormalities with a specific facial appearance. The skeletal abnormalities include bowing of long bones, s-curved leg bones, ribbon-like ribs and a hardening of the skull base, as well as spine deformities. The typical facial features include prominent, protruding eyes, full cheeks, an extremely small lower jaw and a hairy forehead. The condition may affect many bones of the body causing deformities and often short stature. Regular evaluations as well as surgical treatment may be needed to manage symptoms. MNS is thought to follow an X-linked dominant pattern of inheritance and is usually caused by a new change (mutation) in the FLNA gene.
MNS is a congenital condition, meaning it is present from birth. However, different members of the same family can have differences in the severity of their symptoms. Due to this variability, individuals may vary in their age at the time of diagnosis.
Individuals with MNS have a particular facial appearance with prominent, widely spaced eyes (hypertelorism), full cheeks, small facial bones and an unusually small lower jaw (micrognathia). The skull may be slow to develop and the way in which individuals with MNS bring their teeth together (bite) may be abnormal. They may also have misaligned teeth or a partial absence of teeth (oligodontia).
The upper arms and the last bones in the fingers (distal phalanges) may be shorter than normal. One of the short bones of the arm (radius) and of the leg (fibula) may be bowed. The distal (farthest from the body) ends of the long bone of the arm (humerus) and of the two short bones of the leg (tibia, fibula) may be flared. The connection between the long bone of the leg (femur) and the hip may be misaligned (coxa valga), causing an unusual walking pattern (gait).
Individuals with MNS may also have a relatively small chest cavity (thoracic cage) with irregular ribbon-like ribs, a short collarbone (clavicle) and narrow shoulders. The lower part of their chest has a hollow shape (pectus excavatum). The vertebrae may be longer than normal. Spinal abnormalities, like an abnormal curvature of the spine (scoliosis), have been reported. Part of the pelvis (ilium) may also be flared. Short stature is often seen.
Occasionally, dislocation of the hip may occur. Other abnormalities may also be noted. For example, the tube that runs from the kidney to the bladder (ureter) may be abnormally narrow, which can lead to urine retention and kidney problems. There may also be problems with heart structure (congenital heart defects) and high blood pressure in the lungs (pulmonary hypertension).
Individuals with MNS may develop joint disease (osteoarthritis) in the back and/or hip in later years. The shape of the pelvis in females may make normal childbirth difficult for them. Individuals with MNS may be unusually susceptible to respiratory infections.
Intellectual development is normal in individuals with MNS. Some individuals with MNS may have hearing loss.
MNS is more severe and may be lethal in males. While it is lethal in most males during pregnancy or shortly after birth, there are case reports of males with typical features of MNS in their childhood-adolescent years. In these reports, the males were born to healthy parents and were the first in their families to show symptoms. Abnormalities seen in males with MNS include bulging eyes, protrusion of internal organs through the abdominal wall (omphalocele) and major skeletal abnormalities.
MNS is an X-linked dominant genetic disorder caused by an abnormality (mutation) in the FLNA gene which contains instructions for creating a protein called filamin A. The FLNA gene has been mapped to chromosome Xq28.
Filamin A is an important part of the cell cytoskeleton, a network of proteins that gives cells structure and flexibility. Researchers believe that mutations which cause the FLNA gene to become overactive (gain of function) impact its role in skeletal development, but the exact mechanisms that lead to the symptoms seen in MNS are unknown.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further subdivided into many bands that are numbered. For example, “chromosome Xq28” refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
X-linked dominant disorders are caused by a non-working gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the non-working gene for a particular disease. Males with a non-working gene for an X-linked dominant disorder are more severely affected than females and often do not survive.
MNS usually occurs as the result of a new mutation in the FLNA gene that is not inherited, but familial inheritance has been noted in some families.
MNS occurs in females much more often than in males. This is because males with MNS often do not survive to term in pregnancy. Approximately 70 total cases have been reported in the medical literature, but it is likely that there are many more individuals with MNS who haven’t been reported in the medical literature or haven’t been diagnosed.
MNS is diagnosed through clinical and radiographic (ex: X-ray) evaluation and/or molecular genetic testing of the FLNA gene. A positive family history showing X-linked inheritance can also aid in the diagnosis.
Males with MNS typically have clinical features similar to otopalatodigital syndrome type 2. Females with MNS present with significant clinical variability. Some individuals with MNS may show no or few symptoms and are diagnosed in adulthood after learning about an affected relative, whereas others may be diagnosed before or shortly after birth.
If a mother has a known disease-causing (pathogenic) variant in the FLNA gene, a pregnancy can be diagnosed via chorionic villus sampling (CVS) or amniocentesis. Both procedures are invasive and examine fetal DNA to confirm a prenatal diagnosis but differ in timing regarding when they are offered during the pregnancy. Prenatal ultrasounds may be able to detect physical features suggestive of MNS, but molecular genetic testing is required to confirm a diagnosis.
Treatment of MNS is based on addressing individual symptoms. Clinical care can involve multiple specialists, such as orthopedics, cardiology, audiology, dentistry, surgery and nephrology. There is currently no cure for MNS.
Genetic counseling is recommended for patients and their families.
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