NORD wants to thank Angela Hoang, Eric Kil, and Reeny Thomas, who are Master of Science (MSc) students in Human Genetics and Genomic Data Analytics (MSGDA) and NORD Editorial Interns from Keck Graduate Institute, as well as Barbara Bailus, PhD, Assistant Professor of Genetics at Keck Graduate Institute, for their help in writing this report.
Split hand/foot malformation (SHFM) is a limb abnormality that is present at birth. It is marked by the lack of some fingers and toes (ectrodactyly), which gives the body a claw-like shape. Fingers and toes may also be webbed together. SHFM can be inherited as a single abnormality or as a part of syndrome that includes other characteristics. SHFM has a lot of different symptoms and genetic causes, and people who have it can have different levels of how bad it is. Severity can vary even among members of the same family.
Symptom presentation varies from person to person. Most people with SHFM have fewer than five fingers or toes on a hand or foot (oligodactyly). A smaller proportion of individuals affected by SFHM have finger fusing (syndactyly) of multiple fingers on the hands. This type is often called the “lobster claw” type because the third digit is missing and there is a cone-shaped cut that tapers in toward the wrist and splits the hand in half, making it look like a lobster claw. The fingers or parts of fingers that are still there on each side of the cleft are often webbed or joined together. A cleft, or the absence of bones in the hands before the fingers, usually occurs in both hands. A similar deformity commonly occurs in the feet.
In the second type of finger fusing that is linked to split-hand deformity, only the fifth finger is present (monodactyly) and there is no cleft. These types range in how bad they are, and sometimes people in the same family will have cases of more than one type.
A smaller group of people with SHFM may have extra symptoms, such as not having a hand at all, an iris missing from their eye (aniridia), or being deaf.
Individuals with split-hand deformity usually have a normal lifespan and intelligence. Difficulties in physical functioning are related to the severity of the deformity.
Genetic heterogeneity means that split hand/foot malformation has more than one genetic cause. This makes it hard to find a single mutation that causes the condition.
Split hand/foot malformation can be passed down in different ways depending on the family. In some, it is autosomal dominant, in others, autosomal recessive, and in still others, it is X-linked. SHFM also occurs as a result of a random (sporadic) mutation during fertilization or embryonic development. When one limb is affected, the cause is often a new gene mutation. However, when four limbs are affected, the cause is often an inherited gene mutation.
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If a person gets one working gene and one not-working gene for the disease, they will be a carrier for the disease but probably won’t have any symptoms. The chance for two parents who carry the gene to both pass it on to their child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Dominant genetic disorders happen when a disease can be caused by just one copy of a gene that doesn’t work. The gene that doesn’t work can be passed down from either parent or it can be caused by a changed gene in the person who has it. You have a 50% chance of passing on the non-working gene from a parent who has it to their child during each pregnancy. The risk is the same for males and females.
X-linked genetic disorders are conditions that are caused by an X chromosome gene that doesn’t work. They mostly affect men. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Because females have two X chromosomes, only one of them has the gene that doesn’t work, carrier females usually don’t show any symptoms. Men inherit one X chromosome from their mother, and if a man inherits an X chromosome with a gene that doesn’t work, he will get the disease.
Female carriers of an X-linked disorder have a 25% chance during each pregnancy of having a daughter who is also a carrier. There is also a 25% chance of having a daughter who is not a carrier, a 25% chance of having a son who has the disorder, and a 25% chance of having a son who does not have the disorder.
If a man with an X-linked disorder can have children, he will give all of his daughters the gene that doesn’t work, making them carriers. Because men always give their Y chromosome to their sons instead of their X chromosome, a father can’t pass on an X-linked gene to his sons.
SHFM can happen by itself, or it can be a part of a syndrome that affects other parts of the body. Researchers have found twelve different types of SHFM on different human chromosomes. They are still finding new gene locations (loci) all the time. Type 1 isolated split hand/foot malformation symptoms are found in the first eight types of SHFM. Other subtypes are type 2 with long-bone deficiencies. To find SHFM1, look at chromosome 7q21. SHFM2 is on Xq32. SHFM3 is on 10q24. SHFM4 is on 3q27. SHFM5 is on 2q31. and SHFM6 is on 12q13. 11q13, and other loci in the 8q21. 11q22. 3 region. There are additional types of SHFM with long bone deficiency that map to chromosomes 1q42. 2q43, 6q14. 1 and 17p13. 3.
Other types of SHFM with long bone deficiency (SHFLD) are passed down in a way called autosomal dominant inheritance and are caused by specific genes. People with SHFLD often have problems with their tibia and fibula, and this has been linked to three loci. SHFLD1 has been mapped to a region spanning 1q42. 4q43, SHFLD2 to 6q14. 1, and SHFLD3 to a region in 17p13. 1p13. 3. Researchers have found a family where SHFLD3 is linked to the BHLHA9 gene, but they need to do more testing to be sure.
SHFM1 has also been linked to changes in the DLX5 and DLX6 genes. These genes are part of the WNt signaling pathway, which is known to be important for the development of limbs in embryos. In mice that don’t have the DLX5 and DLX6 genes, it has been shown that these genes are involved in ectrodactyly (not having fingers and/or toes). These mice presented with significant forms of ectrodactyly.
SHFM2 shows a unique X-linked inheritance of ectrodactyly that has only been seen in one family that is related by blood. Further linkage analysis mapped this association to Xp26, and possible gene candidates are FGF13 and TONDU.
SHFM3 is found in the 10q24 region of chromosome 10, and the genetic change that causes this is a tandem duplication. This duplication actually accounts for 20% of SHFM cases. There are several genes affected by the duplication: DACTYLIN (SFHM3), BTRC, POLL, FGF8, and LBX1.
SHFM4 is caused by a loss of function mutation in the TP63 gene. TP63 has been shown to be important in tissue layering (epithelial stratification). It is uniquely inherited in an autosomal dominant fashion. Mice lacking p63 protein have been shown to have significant defects in proper limb development and/or limb shortening.
SHFM5 is seen in individuals who have deletions of the entire HOXD cluster. HOX genes are important for limb development and proper growth. Deletions of HOX genes can be causative for many growth aberrations including ectrodactyly and monodactyly.
SHFM6 is another subtype of ectrodactyly and is caused by mutations in the 12q13 locus. Only three families have been reported to have it. It is caused by autosomal recessive mutations in the DLX5 and Wnt genes. Mutations in Wnt genes have been shown to be necessary, but not sufficient in producing SHMF.
Changes in the ZAK gene are known to cause SHFM7 with mesoaxial polydactyly, which is when an extra finger or toe is added (SHFMMP). If a person has more than five digits, not counting the thumb or toe, and some bones have fused together, this is called mesoaxial polydactyly. Homozygous missense mutations and homozygous intragenic deletions have also been shown in affected patients.
SHFM8 is another form of ectrodactyly with mild-to-severe symptoms that is caused by mutations in the EPS15L1 gene. There have been reports of frameshift deletions, nonsense mutations, and other changes that cause EPS15L1 protein levels to drop. The EPS15L1 protein has a unique role in embryonic development and neurogenesis.
Because SHFM can be passed down in three different ways—autosomal dominant, autosomal recessive, or X-linked—the rate at which it affects boys and girls is about the same. The X-linked SHFM cases typically manifest in males. The total frequency of all SHFM cases is approximately 1 out of every 90,000-100,000 live births, worldwide.
Lobster claw syndrome, also known as split hand/foot malformation (SHFM), is a rare congenital limb deformity. It is characterized by missing fingers and toes that give the hands and feet a claw-like appearance. But what exactly causes this unusual condition?
SHFM has a number of different genetic causes and inheritance patterns The most common varieties are
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SHFM1 – caused by mutations in the DLX5 and DLX6 genes on chromosome 7q21. These genes are part of the WNT signaling pathway that controls limb development. SHFM1 follows an autosomal dominant inheritance pattern.
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SHFM3 – caused by a duplication on chromosome 10q24 involving the genes DACTYLIN, BTRC, POLL, FGF8, and LBX1. This duplication accounts for around 20% of SHFM cases and is inherited in an autosomal dominant manner.
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SHFM4 – caused by mutations in the TP63 gene on chromosome 3q27. TP63 is important for epithelial development. SHFM4 is also autosomal dominant.
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SHFM5 – caused by deletions of the entire HOXD gene cluster on chromosome 2q31. The HOX genes control growth and development of the limbs and other body parts.
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X-linked SHFM – mapped to the Xq26 region Primarily affects males when inherited from carrier mothers
Some key points about the genetic causes of lobster claw syndrome:
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There are at least 7 different genetic types involving mutations on various chromosomes. This is known as genetic heterogeneity.
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Autosomal dominant is the most common inheritance pattern, meaning only one mutated gene copy is needed to cause the disorder.
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Many of the involved genes (WNT, FGF, HOX, TP63) play important roles in limb and skeletal development.
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Chromosomal duplications, deletions, and rearrangements that disrupt these genes can lead to SHFM.
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The specific mutation and inheritance pattern can vary even within the same family.
In autosomal recessive SHFM, which is less common, two mutated copies of a gene are required to cause lobe ster claw syndrome. Both parents must be carriers. Some forms of autosomal recessive SHFM include:
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SHFM6 – caused by mutations in DLX5 and WNT genes on chromosome 12q13. Reported in 3 families.
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SHFM with mesoaxial polydactyly – caused by mutations in the ZAK gene. Has extra digits along with missing digits.
The lobster claw split hand/foot appearance occurs because certain bones in the hands and feet fail to fully develop in utero. This causes missing or partially formed fingers and toes, with fusion of the remaining digits. The specific bones affected determine the severity and pattern of abnormalities:
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Central ray deficiencies – central digits like the 3rd finger missing, leaving cleft hand with 2 lobes. Most common.
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Lateral ray deficiencies – Pinky or thumb missing, other digits fused.
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Complete ray deficiencies – Entire digit missing, leaving gap in hand or foot.
Environmental factors are not believed to play a role in causing SHFM. The limb deformities arise very early in embryonic development as a result of the genetic mutations affecting bone growth.
While the lobster claw defect is present at birth, SHFM is not always inherited. Around half of cases occur spontaneously due to a new mutation.
Frequency of Entity Occurrences:
- split hand/foot malformation (SHFM) – 11
- chromosome – 5
- autosomal dominant – 4
- limb – 4
- gene – 4
- digits – 3
- inherited – 2
- mutations – 2
- toes – 2
- bones – 2
- causes – 2
- fingers – 2
- lobster claw syndrome – 2
Disorders with Similar Symptoms
This disorder falls under the category of “ectodermal dysplasia”. This group of disorders is defined by ectrodactyly, the lack of tear ducts, cleft lip and/or palate, and hair loss on the scalp, eyelashes, and eyebrows.
- A list of disorders associated with ectrodactyly include:
- Ectrodactyly-cleft palate syndrome
- Ectrodactyly-ectodermal dysplasia-clefting syndrome
- Ectrodactyly-fibular aplasia/hypoplasia syndrome
- Ectrodactyly-ectodermal dysplasia-macular dystrophy syndrome
- Ectrodactyly-polydactyly
For more information on these disorders, search for “ectodermal dysplasia” in the Rare Disease Database.
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SHFM is usually diagnosed by physical features present at birth. The presence of abnormal number of toes and finger dysplasia is usually obvious during initial evaluations. Genetic testing for the genes previously discussed is available to further support the initial diagnosis.
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Treatment Reconstructive surgery can be performed to improve function and appearance when applicable. Prosthetics are also available for patients.
Genetic counseling is recommended for affected individuals and their families.
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Lobster Claw Syndrome
What is ectrodactyly lobster claw syndrome?
The hands and feet of people with ectrodactyly are often described as “claw-like” and may include only the thumb and one finger (usually either the little finger, ring finger, or a syndactyly of the two) with similar abnormalities of the feet. It is sometimes referred to as “lobster claw” syndrome.
Is lobster claw hand a symptom of EEC syndrome?
1. Cyriac MJ, Lashpa E. Lobster-claw hand: A manifestation of EEC syndrome. Indian J Dermatol Venereol Leprol. 2006;72:54–6. [ PubMed] [ Google Scholar] 2. Wolfe SW. Deformities of hand and fingers: Central hand deficiencies.
What is lobster claw?
Maldevelopment of the central rays of the limbs may produce longitudinal splitting of the extremities. Split hand or foot may be sporadic, but autosomal dominant and recessive forms of this condition, sometimes termed the “lobster claw” defect, have been described. The defect also occurs as part of several syndromes.
Can SFHM cause a lobster claw?
A smaller proportion of individuals affected by SFHM have finger fusing (syndactyly) of multiple fingers on the hands. This is often referred to as the “lobster claw” variety where the third digit is absent and replaced with a cone-shaped cleft that tapers in toward the wrist and divides the hand into two parts resembling a lobster claw.