Melnick Needles Syndrome

Disease Overview

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.

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Synonyms

• Melnick-Needles osteodysplasty
• MNS
• osteodysplasty of Melnick and Needles

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Subdivisions

• No subdivisions found

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Signs & Symptoms

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.

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Causes

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.

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Affected populations

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.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Melnick-Needles syndrome. Comparisons may be useful for a differential diagnosis:

Multiple epiphyseal dysplasia (MED) is a hereditary bone disorder that affects females and males in equal numbers. It can either have an autosomal recessive or autosomal dominant pattern of inheritance. Symptoms begin between two and five years of age with the appearance of a waddling gait. Individuals with MED may experience pain because of joint disease (osteoarthritis). Body size tends to be almost normal, except for the hands and feet which are disproportionately small. (For more information on this condition, choose “rMED or dMED” as your search terms in the Rare Disease Database.)

Otopalatodigital syndrome type 2 (OPD2) is an X-linked disorder that involves skeletal abnormalities and a particular facial appearance. Like MNS, it is more severe and often lethal in males. However, females with OPD2 typically have milder features in comparison to those with Melnick-Needles syndrome. (For more information on this condition, choose “otopalatodigital syndrome” as your search term in the Rare Disease Database.)

Frank Ter Haar syndrome is an autosomal recessive disorder that also involves skeletal abnormalities, congenital heart defects and a particular facial appearance. It was previously thought to be a form of Melnick-Needles syndrome. However, it affects females and males in equal numbers.

Shprintzen-Goldberg syndrome (SGS) is a rare connective tissue disorder that affects females and males in equal numbers. It has an autosomal dominant pattern of inheritance. Individuals with SGS have similar skeletal features, particularly in the vertebrae, but they have differences in the fusion of skull bones (craniosynostosis) and intellectual disability not generally seen in Melnick-Needles syndrome. (For more information on this condition, choose “Shprintzen Goldberg syndrome” as your search term in the Rare Disease Database.)

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Diagnosis

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.

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Standard Therapies

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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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Jones KL. Ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co.; 1997:588-89.

Gorlin RJ, Cohen MMJr, Levin LS. Eds. Syndromes of the Head and Neck. 3rd ed. London, UK: Oxford University Press; 1990:277-80.

JOURNAL ARTICLES
Oh CH, Lee CH, Kim SY, et al. A family of Melnick-Needles syndrome: a case report. BMC Pediatr.2020;20:391.

Spencer C, Lombaard H, Wise A, et al. A recurrent mutation causing Melnick-Needles syndrome in females confers a severe, lethal phenotype in males. Am J Med Genet.2018;176:980-984.

Jung S, Wermker, K. et al. Orthognathic surgery in Melnick-Needles-syndrome. Case report and review of the literature. Int J Oral Maxillofac Surg.2012; 41:309-312.

Akin L, Adal E, Akin MA, et al. Melnick-Needles syndrome associated with growth hormone deficiency: a case report. J Clin Res Ped Endo. 2009;1(5):248-51.

Robertson SP. Otopalatodigital syndrome spectrum disorders: otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia and Melnick-Needles syndrome. Eur J Hum Genet.2007;15:3-9.

Robertson SP, Twigg SR, Sutherland-Smith AJ, et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet.2003;33:487-91.

Kristiansen M, Knudsen G. et al. Phenotypic variation in Melnick-Needles syndrome is not reflected in X inactivation patterns from blood or buccal smear. Am J Med Genet.2002;108:120-127.

Verloes A, Lesenfants S, Barr M, et al. Fronto-otopalatodigital osteodysplasia: clinical evidence for a single entity encompassing Melnick-Needles syndrome, otopalataodigital syndrome types 1 and 2, and frontometaphyseal dysplasia. Am J Med Genet.2000;90:407-22.

Albano LM, Kim CA, Lee VK, et al. Clinical and radiological aspects in Melnick-Needles syndrome. Rev Hosp Clin Fac Med Sao Paulo.1999;54:69-72.

Nishimura G, Horiuchi T, Kim OH, et al. Atypical skeletal changes in otopalatodigital syndrome type II: phenotypic overlap among otopalatodigital syndrome type II, boomerang dysplasia, atelosteogenesis type I and type III, and lethal male phenotype of Melnick-Needles syndrome. Am J Med Genet.1997;73:132-38.

Robertson S, Gunn T, Allen B, et al. Are Melnick-Needles syndrome and oto-palato-digital syndrome type II allelic? Observations in four-generation kindred. Am J Med Genet.1997;71:341-47.

Neou P, Kyrkanides S, Goureli E, et al. Melnick-Needles syndrome in a mother and her son. Genet Cous. 1996;7;123-29.

van der Lely H, Robben S, et al. Melnick-Needles syndrome (osteodysplasty) in an older male – report of a case and a review of the literature. Brit J Radiol.1991;64:852-854.

Donnenfeld AE, Conard KA, et al. Melnick-Needles syndrome in males: a lethal multiple congenital anomalies syndrome. Am J Med Genet.1987;27:159-173.

Krajewska-Walasek M, Winkielman J, Gorlin RJ. Melnick-Needles syndrome in males. Am J Med Genet.1987;27:153-158.

Zackai EH, Donnenfeld AE, et al. The male Melnick-Needles syndrome phenotype. Am J Hum Genet.1986;39: A88.

von Oeyen PT, Holmes LB, et al. Omphalocele and multiple severe congenital anomalies associated with osteodysplasty (Melnick-Needles syndrome). Am J Med Genet.1982;13:453-463.

Theander G, Ekberg O. Congenital malformations associated with maternal osteodysplasty. Acta Radiol Diagn.1981;22:369-377.

von Oeyen PT, Holmes LB, et al. Melnick-Needles syndrome with omphalocele and renal hypoplasia. Am J Hum Genet.1981;33:92A.

Coste F, Maroteaux P. et al. Osteodysplasty (Melnick and Needles’ syndrome): report of a case. Ann Rheum.1968;27:360-366.

Melnick JC, Needles CF. An undiagnosed bone dysplasia. A 2-family study of 4 generations and 3 generations. Am J Roentgenology.1966;97-1.

INTERNET
Robertson S. X-Linked Otopalatodigital Spectrum Disorders. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Last Updated 10/3/2019. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1393/ Accessed March 31, 2022.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Melnick-Needles Syndrome; MNS. Entry No: 309350. Last Updated 10/14/2015. Available at: https://omim.org/entry/309350 Accessed March 31, 2022.

Melnick-Needles syndrome. Orphanet. Last Updated: May 2015. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2484
Accessed March 31, 2022.

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