The syndrome was first reported in an eight-year-old boy, but very few cases have been reported since then. The syndrome is detected by abnormalities noted at birth involving the head, limbs, heart, ears, and skin. It is characterized by premature closure of the fibrous joints between certain bones of the skull in a process known as craniosynostosis. As documented in the first case, the victim tends to suffer from cyanosis and other respiratory and breathing infections, all before the age of one. Body development subsequently slows down, but some problems can be fixed under proper guidance, such as learning to walk with special crutches by five years of age. Craniofacial problems are present that have no effect on the patient's intelligence and mental growth.

Most problems resulting from the syndrome are physical. It causes acrocephaly, making the head appear pointed, and webbing or syndactyly of certain toes or fingers.

Many of the physical features associated with the disorder are congenital. Characteristic craniofacial abnormalities typically include a long, narrow head that is disproportionate to the body size, a broad and prominent forehead, and a triangular-shaped face with a hypoplastic midface, pointed chin, prominent mouth, fleshy tipped upturned nose, large ears, and full lips. The teeth may be abnormally crowded together in some affected individuals.

Individuals with 3-M syndrome suffer from severe prenatal growth retardation due to growth delays during fetal development resulting in a low birth weight. Growth delays continue after birth throughout childhood and adolescence, ultimately leading to a short stature.

Sakati–Nyhan–Tisdale syndrome, also called acrocephalopolysyndactyly type III, is a rare genetic disorder that has been associated with abnormalities in the bones of the legs, congenital heart defects and craniofacial defects. The syndrome belongs to a group of rare genetic disorders known as acrocephalopolysyndactyly or ACPS, for short.

Carpenter syndrome presents several features:

- Tower-shaped skull (craniosynostosis)

- Additional or fused digits (fingers and toes)

- Obesity

- Reduced height

Intellectual disability is also common with the disorder, although some patients may have average intellectual capacity.

Acrocallosal syndrome (also known as ACLS) is a rare autosomal recessive syndrome characterized by corpus callosum agenesis, polydactyly, multiple dysmorphic features, motor and mental retardation, and other symptoms. The syndrome was first described by Albert Schinzel in 1979.

It is associated with "GLI3".

Acrocallosal syndrome (ACLS, ACS, Schinzel-Type, Hallux-duplication) is a rare, heterogeneous [3] autosomal recessive disorder first discovered by Albert Schinzel (1979) in a 3-year-old boy . To inherit ACLS, one gene copy from each parent must contain a mutation somewhere in the KIF7 gene and be passed on to the child [3]. Characteristics of this syndrome include absence or poor development of the area connecting the left and right parts of the brain, an abnormally large head, increased distance between facial features (eyes), poor motor skills, mental retardation [2], extra fingers and toes, many facial deformities [3], and cleft palate [5]. This is considered a rare disorder and is placed on the NIH Office of Rare Diseases (fewer than 200,000 cases) rare disease list [8]. Lifespan may range from stillbirth to normal expectancy depending on pregnancy complications and severity of the disorder [2,3,5]. In mild cases, the subjects have been shown to live relatively normal lives, but with developmental delays [2].

Carpenter Syndrome belongs to a group of rare genetic disorders known as acrocephalopolysyndactyly, abbreviated ACPS (RN, 2007). There were originally five types of ACPS, but this number has been decreased because they have been found to be closely related to one another or to other disorders (Paul A. Johnson, 2002).

The most common physical manifestation of Carpenter Syndrome is early fusing of the fibrous cranial sutures which results in an abnormally pointed head. The fusion of the skull bones is evident from birth (National Organization for Rare Disorders, Inc., 2008). Babies’ mobile cranial bones form a cone shape as the pass through the birth canal and soon thereafter return to a normal shape; however, a baby affected by carpenter syndrome maintains a cone shaped head.

A baby affected by Carpenter Syndrome will also display malformations of the face. An individual affected by the syndrome may have broad cheeks, a flat nasal bridge, and a wide upturned nose with abnormally large nasal openings. Their ears will most commonly be low, unevenly set, and malformed in structure. In addition to these facial abnormalities, individuals also have an underdeveloped maxilla and/ or mandible with a highly arched and narrow palate which makes speech a very difficult skill to master. Teeth are usually very late to come in and will be undersized and spaced far apart (Carpenter Syndrome-description).

Other physical abnormalities often associated with Carpenter Syndrome include extra digits. Extra toes are more commonly seen than fingers. Often both the toes and fingers are webbed, a process that occurs before the sixth week gestational period. Often their digits will be abnormally short, and the fingers are commonly missing an interphalangeal joint. Roughly half of the babies born with Carpenter Syndrome have some type of heart defect, and seventy five percent of individuals with this disease will experience some degree of development delay due to mild mental retardation (Carpenter Syndrome-description).

Acrocephalosyndactylia (or acrocephalosyndactyly) is the common presentation of craniosynostosis and syndactyly.

It has several different types:

- type 1 - Apert syndrome

- type 2 - Crouzon syndrome

- type 3 - Saethre-Chotzen syndrome

- type 5 - Pfeiffer syndrome

A related term, "acrocephalopolysyndactyly" (ACPS), refers to the inclusion of polydactyly to the presentation. It also has multiple types:

- type 1 - Noack syndrome; now classified with Pfeiffer syndrome

- type 2 - Carpenter syndrome

- type 3 - Sakati-Nyhan-Tisdale syndrome

- type 4 - Goodman syndrome; now classified with Carpenter syndrome

- type 5 - Pfeiffer syndrome

It has been suggested that the distinction between "acrocephalosyndactyly" versus "acrocephalopolysyndactyly" should be abandoned.

DKC can be characterized by cutaneous pigmentation, premature graying, of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, testicular atrophy in the male carriers, and predisposition to cancer. Many of these symptoms are characteristic of geriatrics, and those carrying the more serious forms of the disease often have significantly shortened lifespans.

Age: The mucocutaneous features of DKC typically develop between ages 5 and 15 years. The median age of onset of the peripheral cytopenia is 10 years.

Sex: The male-to-female ratio is approximately 3:1.

Physical: The triad of reticulated hyperpigmentation of the skin, nail dystrophy, and leukoplakia characterizes DKC. The syndrome is clinically heterogeneous; in addition to the diagnostic mucocutaneous features and bone marrow failure, affected individuals can have a variety of other clinical features.

Cutaneous findings:

The primary finding is abnormal skin pigmentation, with tan-to-gray hyperpigmented or hypopigmented macules and patches in a mottled or reticulated pattern. Reticulated pigmentation occurs in approximately 90% of patients. Poikilodermatous changes with atrophy and telangiectasia are common.

The cutaneous presentation may clinically and histologically resemble graft versus host disease. The typical distribution involves the sun-exposed areas, including the upper trunk, neck, and face. Other cutaneous findings may include alopecia of the scalp, eyebrows, and eyelashes; premature graying of the hair; hyperhidrosis; hyperkeratosis of the palms and soles; and adermatoglyphia (loss of dermal ridges on fingers and toes).

Nail findings:

Nail dystrophy is seen in approximately 90% of patients, with fingernail involvement often preceding toenail involvement.

Progressive nail dystrophy begins with ridging and longitudinal splitting. Progressive atrophy, thinning, pterygium, and distortion eventuate in small, rudimentary, or absent nails.

Mucosal findings:

Mucosal leukoplakia occurs in approximately 80% of patients and typically involves the buccal mucosa, tongue, and oropharynx. The leukoplakia may become verrucous, and ulceration may occur. Patients also may have an increased prevalence and severity of periodontal disease.

Other mucosal sites may be involved (e.g., esophagus, urethral meatus, glans penis, lacrimal duct, conjunctiva, vagina, anus). Constriction and stenosis can occur at these sites, with subsequent development of dysphagia, dysuria, phimosis, and epiphora.

Bone marrow failure:

Approximately 90% have peripheral cytopenia of one or more lineages. In some cases, this is the initial presentation, with a median age of onset of 10 years.

Bone marrow failure is a major cause of death, with approximately 70% of deaths related to bleeding and opportunistic infections as a result of bone marrow failure.

Pulmonary complications:

Approximately 20% of individuals with DKC develop pulmonary complications, including pulmonary fibrosis and abnormalities of pulmonary vasculature.

The recommendation is that DKC patients avoid taking drugs with pulmonary toxicity (e.g., busulfan) and that they have their lungs shielded from radiation during BMT.

Increased risk of malignancy:

Patients have an increased prevalence of malignant mucosal neoplasms, particularly squamous cell carcinoma of the mouth, nasopharynx, esophagus, rectum, vagina, or cervix. These often occur within sites of leukoplakia.

The prevalence of squamous cell carcinoma of the skin is also increased. Other malignancies reported include Hodgkin lymphoma, adenocarcinoma of the gastrointestinal tract, and bronchial and laryngeal carcinoma.

Malignancy tends to develop in the third decade of life.

Neurologic system findings: Patients may have learning difficulties and mental retardation.

Ophthalmic system findings: DKC reportedly is associated with conjunctivitis, blepharitides, and pterygium. Lacrimal duct stenosis resulting in epiphora (i.e., excessive tearing) occurs in approximately 80% of patients.

Skeletal system findings: Patients may have mandibular hypoplasia, osteoporosis, avascular necrosis, and scoliosis.

Gastrointestinal system findings: These may include esophageal webs, hepatosplenomegaly, enteropathy, and cirrhosis.

Genitourinary system findings:: Hypospastic testes, hypospadias, and ureteral stenosis are reported.

Female carriers: Female carriers of DKC may have subtle clinical features. One study showed that 3 of 20 female carriers had clinical features that included a single dystrophic nail, a patch of hypopigmentation, or mild leukoplakia.

The most common presentation of Milroy Disease is bilateral lower extremity lymphedema, and may also be accompanied by hydrocele.

Milroy's disease (MD) is a familial disease characterized by lymphedema, commonly in the legs, caused by congenital abnormalities in the lymphatic system. Disruption of the normal drainage of lymph leads to fluid accumulation and hypertrophy of soft tissues. It is also known as Milroy disease, Nonne-Milroy-Meige syndrome and hereditary lymphedema.

It was named by Sir William Osler for William Milroy, a Canadian physician, who described a case in 1892, though it was first described by Rudolf Virchow in 1863.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder which manifests with insulin resistance, absence of subcutaneous fat and muscular hypertrophy. Homozygous or compound heterozygous mutations in four genes are associated with the four subtypes of CGL. The condition appears in early childhood with accelerated linear growth, quick aging of bones, and a large appetite. As the child grows up, acanthosis nigricans (hyperpigmentation and thickening of skin) will begin to present itself throughout the body – mainly in the neck, trunk, and groin. The disorder also has characteristic features like hepatomegaly or an enlarged liver which arises from fatty liver and may lead to cirrhosis, muscle hypertrophy, lack of adipose tissue, splenomegaly, hirsutism (excessive hairiness) and hypertriglyceridemia. Fatty liver and muscle hypertrophy arise from the fact that lipids are instead stored in these areas; whereas in a healthy individual, lipids are distributed more uniformly throughout the body subcutaneously. The absence of adipose tissue where they normally occur causes the body to store fat in the remaining areas. Common cardiovascular problems related to this syndrome are cardiac hypertrophy and arterial hypertension (high blood pressure). This disorder can also cause metabolic syndrome. Most with the disorder also have a prominent umbilicus or umbilical hernia. Commonly, patients will also have acromegaly with enlargement of the hands, feet, and jaw. After puberty, additional symptoms can develop. In women, clitoromegaly and polycystic ovary syndrome can develop. This impairs fertility for women, and only a few documented cases of successful pregnancies in women with CGL exist. However, the fertility of men with the disorder is unaffected.

Onset of late infantile GM1 is typically between ages 1 and 3 years.

Neurological symptoms include ataxia, seizures, dementia, and difficulties with speech.

Congenital generalized lipodystrophy (also known as Berardinelli–Seip syndrome) is an extremely rare autosomal recessive skin condition, characterized by an extreme scarcity of fat in the subcutaneous tissues. It is a type of lipodystophy disorder where the magnitude of fat loss determines the severity of metabolic complications. Only 250 cases of the condition have been reported, and it is estimated that it occurs in 1 in 10 million people worldwide.

Symptoms of early infantile GM1 (the most severe subtype, with onset shortly after birth) may include neurodegeneration, seizures, liver enlargement (hepatomegaly), spleen enlargement (splenomegaly), coarsening of facial features, skeletal irregularities, joint stiffness, distended abdomen, muscle weakness, exaggerated startle response to sound, and problems with gait.

About half of affected patients develop cherry-red spots in the eye.

Children may be deaf and blind by age 1 and often die by age 3 from cardiac complications or pneumonia.

- Autosomal recessive disorder; beta-galactosidase deficiency; neuronal storage of GM1 ganglioside and visceral storage of galactosyl oligosaccharides and keratan sulfate.

- Early psychomotor deterioration: decreased activity and lethargy in the first weeks; never sit; feeding problems - failure to thrive; visual failure (nystagmus noted) by 6 months; initial hypotonia; later spasticity with pyramidal signs; secondary microcephaly develops; decerebrate rigidity by 1 year and death by age 1–2 years (due to pneumonia and respiratory failure); some have hyperacusis.

- Macular cherry-red spots in 50% by 6–10 months; corneal opacities in some

- Facial dysmorphology: frontal bossing, wide nasal bridge, facial edema (puffy eyelids); peripheral edema, epicanthus, long upper lip, microretrognathia, gingival hypertrophy (thick alveolar ridges), macroglossia

- Hepatomegaly by 6 months and splenomegaly later; some have cardiac failure

- Skeletal deformities: flexion contractures noted by 3 months; early subperiosteal bone formation (may be present at birth); diaphyseal widening later; demineralization; thoracolumbar vertebral hypoplasia and beaking at age 3–6 months; kyphoscoliosis. *Dysostosis multiplex (as in the mucopolysaccharidoses)

- 10–80% of peripheral lymphocytes are vacuolated; foamy histiocytes in bone marrow; visceral mucopolysaccharide storage similar to that in Hurler disease; GM1 storage in cerebral gray matter is 10-fold elevated (20–50-fold increased in viscera)

- Galactose-containing oligosacchariduria and moderate keratan sulfaturia

- Morquio disease Type B: Mutations with higher residual beta-galactosidase activity for the GM1 substrate than for keratan sulfate and other galactose-containing oligosaccharides have minimal neurologic involvement but severe dysostosis resembling Morquio disease type A (Mucopolysaccharidosis type 4).

Affected newborns generally have striking neurological defects and seizures. Severely impaired development is common, but disturbances in motor functions may not appear until later in life.

Infants with microcephaly are born with either a normal or reduced head size. Subsequently, the head fails to grow, while the face continues to develop at a normal rate, producing a child with a small head and a receding forehead, and a loose, often wrinkled scalp. As the child grows older, the smallness of the skull becomes more obvious, although the entire body also is often underweight and dwarfed. Development of motor functions and speech may be delayed. Hyperactivity and intellectual disability are common occurrences, although the degree of each varies. Convulsions may also occur. Motor ability varies, ranging from in some to spastic quadriplegia in others.

Children with constitutional delay of growth and puberty (CDGP), the most common cause of short stature and pubertal delay in males, typically have slowed linear growth within the first 3 years of life. In this variant of normal growth, linear growth velocity and weight gain slows beginning as young as age 3–6 months, resulting in downward crossing of growth percentiles, which often continues until age 2–3 years. At that time, growth resumes at a normal rate, and these children grow either along the lower growth percentiles or beneath the curve but parallel to it for the remainder of the prepubertal years.

At the expected time of puberty, the height of children with CDGP begins to drift further from the growth curve because of delay in the onset of the pubertal growth spurt. Catch-up growth, onset of puberty, and pubertal growth spurt occur later than average, resulting in normal adult stature and sexual development. Although CDGP is a variant of normal growth rather than a disorder, delays in growth and sexual development may contribute to psychological difficulties, warranting treatment for some individuals. Recent studies have suggested that referral bias is largely responsible for the impression that normal short stature per se is a cause of psycho-social problems; non-referred children with short stature do not differ from those with more normal stature in school performance or socialization.

Constitutional delay of growth and puberty (CDGP) is a term describing a temporary delay in the skeletal growth and thus height of a child with no physical abnormalities causing the delay. Short stature may be the result of a growth pattern inherited from a parent (familial) or occur for no apparent reason (idiopathic). Typically at some point during childhood, growth slows down, eventually resuming at a normal rate. CDGP is the most common cause of short stature and delayed puberty.

Microcephaly is a medical condition in which the brain does not develop properly resulting in a smaller than normal head. Microcephaly may be present at birth or it may develop in the first few years of life. Often people with the disorder have an intellectual disability, poor motor function, poor speech, abnormal facial features, seizures, and dwarfism.

The disorder may stem from a wide variety of conditions that cause abnormal growth of the brain, or from syndromes associated with chromosomal abnormalities. A homozygous mutation in one of the "microcephalin" genes causes primary microcephaly. It serves as an important neurological indication or warning sign, but no uniformity exists in its definition. It is usually defined as a head circumference (HC) more than two standard deviations below the mean for age and sex. Some academics advocate defining it as head circumference more than three standard deviations below the mean for the age and sex.

There is no specific treatment that returns the head size to normal. In general, life expectancy for individuals with microcephaly is reduced and the prognosis for normal brain function is poor. Occasionally, some will grow normally and develop normal intelligence.

Hemihypertrophy, now more commonly referred to as hemihyperplasia in the medical literature, is a condition in which one side of the body or a part of one side of the body is larger than the other to an extent considered greater than the normal variation. As it is difficult to establish a set clinical criteria for diagnosis of hemihyperplasia, the dictum is often used that the clinician should be able to see the asymmetry "from the end of the bed".

Hemihyperplasia is a congenital overgrowth disorder and the asymmetry can range from mild to severe. It is important to establish a diagnosis because hemihyperplasia is associated with an increased risk for embryonal tumors, mainly Wilms tumor and hepatoblastoma. Due to the heightened tumor risk, there is a tumor screening protocol that is recommended for all children with isolated hemihyperplasia and Beckwith-Wiedemann Syndrome. Some of the other syndromes associated with hemihyperplasia may also follow this tumor surveillance protocol. The recommended tumor surveillance protocol is:

1. Any child with suspected isolated hemihyperplasia should be referred to a clinical geneticist for evaluation.

2. Abdominal ultrasound every 3 months until 7 years

3. Serum alpha fetoprotein measurement every 3 months until 4 years

4. Daily caretaker abdominal examination at the discretion of the provider/parent

In some cases, children with hemihyperplasia may have different leg lengths. There are two main surgical options for the treatment of uneven leg lengths- shortening and lengthening. Epiphysiodesis, which involves removing part of the growth plate of the longer leg, allowing the shorter leg to "catch up", may be performed on patients still able to grow. Bone resection is performed on patients who have no growth left and involves removing part of the bone. Leg lengthening procedures are more painful, involving the insertion of pins to be turned, moving parts of the bone apart (Ilizarov's Method). This process is reserved mainly for patients with a discrepancy greater than 4 cm, although some leg lengthening procedures are now done cosmetically. Non-surgical options include attachment of a lift to the shoe, allowing the patient to walk normally.

Children with hemihypertrophy may also develop scoliosis, a curvature of the spine.

Hemifacial hyperplasia is believed to be a minor form of hemihypertrophy.

The precise symptoms of a primary immunodeficiency depend on the type of defect. Generally, the symptoms and signs that lead to the diagnosis of an immunodeficiency include recurrent or persistent infections or developmental delay as a result of infection. Particular organ problems (e.g. diseases involving the skin, heart, facial development and skeletal system) may be present in certain conditions. Others predispose to autoimmune disease, where the immune system attacks the body's own tissues, or tumours (sometimes specific forms of cancer, such as lymphoma). The nature of the infections, as well as the additional features, may provide clues as to the exact nature of the immune defect.

A number of syndromes escape formal classification but are otherwise recognisable by particular clinical or immunological features.

1. Wiskott–Aldrich syndrome

2. DNA repair defects not causing isolated SCID: ataxia-telangiectasia, ataxia-like syndrome, Nijmegen breakage syndrome, Bloom syndrome

3. DiGeorge syndrome (when associated with thymic defects)

4. Various immuno-osseous dysplasias (abnormal development of the skeleton with immune problems): cartilage–hair hypoplasia, Schimke syndrome

5. Hermansky–Pudlak syndrome type 2

6. Hyper-IgE syndrome

7. Chronic mucocutaneous candidiasis

8. Hepatic venoocclusive disease with immunodeficiency (VODI)

9. XL-dyskeratosis congenita (Hoyeraal-Hreidarsson syndrome)