Clinical Features of Cystic Fibrosis

The clinical features of cystic fibrosis are summarized below:

Respiratory Tract.Cough is the most constant symptom of pulmonary involvement. At first, the cough may be dry and hacking, but eventually it becomes loose and productive. In older patients, the cough is most prominent on arising in the morning or after activity. Expectorated mucus is usually purulent. Some patients remain asymptomatic for long periods or seem to have prolonged but intermittent acute respiratory infections. Others acquire a chronic cough in the 1st weeks of life, or they have pneumonia repeatedly.

Extensive bronchiolitis is attended by wheezing, which is a frequent symptom during the 1st years of life. As lung disease slowly progresses, exercise intolerance, shortness of breath, and failure to gain weight or grow are noted. Exacerbations of lung symptoms, presumably owing to more active airways infection, eventually require repeated hospitalizations for effective treatment.

Cor pulmonale, respiratory failure, and death eventually supervene unless lung transplantation is accomplished. Colonization with Burkholderia cepacia and other multidrug-resistant organisms may be associated with particularly rapid pulmonary deterioration and death.

Early physical findings include increased anteroposterior diameter of the chest, generalized hyperresonance, scattered or localized coarse crackles, and digital clubbing. Expiratory wheezes may be heard, especially in young children.

Even though the paranasal sinuses are virtually always opacified radiographically, acute sinusitis is infrequent. Nasal obstruction and rhinorrhea are common, caused by inflamed, swollen mucous membranes or, in some cases, nasal polyposis. Nasal polyps are most troublesome between 5 and 20 yr of age.

Clinical Manifestations of Osteogenesis Imperfecta

Osteogenesis imperfecta has the triad of fragile bones, blue sclerae, and early deafness. OI was once divided into “congenita,” the forms detectable at birth, and “tarda,” the forms detectable later in childhood; this did not account for the variability of OI.

The Sillence classification divides OI into four types based on clinical and radiographic criteria. Additional types have been proposed based on histologic distinctions.

Osteogenesis Imperfecta Type I (Mild):
This form is sufficiently mild that it is often found in large pedigrees. Many type I families have blue sclerae, recurrent fractures in childhood, and presenile hearing loss (30–60%). Both types I and IV are divided into A and B subtypes, depending on the absence (A) or presence (B) of dentinogenesis imperfecta. Other possible connective tissue abnormalities include easy bruising, joint laxity, and mild short stature compared with family members. Fractures result from mild to moderate trauma and decrease after puberty.

Osteogenesis Imperfecta Type II (Perinatal Lethal):
These infants may be stillborn or die in the 1st yr of life. Birthweight and length are small for gestational age. There is extreme fragility of the skeleton and other connective tissues. There are multiple intrauterine fractures of long bones, which have a crumpled appearance on radiographs. There are striking micromelia and bowing of extremities; the legs are held abducted at right angles to the body in the “frog-leg position.” Multiple rib fractures create a beaded appearance and the small thorax contributes to respiratory insufficiency. The skull is large for body size with enlarged anterior and posterior fontanelles. Sclerae are dark blue-gray

Shwachman-Diamond Syndrome

Shwachman-Diamond syndrome (SDS) is inherited in an autosomal recessive manner; it occurs in all racial and ethnic groups. Essential diagnostic criteria are exocrine pancreatic insufficiency and variable hematologic cytopenias due to marrow failure.

Pathology
The mutant gene SBDS maps to chromosome 7q11 and is responsible for the multisystem, pleiotropic phenotype in 90% of cases. Pancreatic insufficiency is due to failure of pancreatic acinar development. Fatty replacement of pancreatic tissue is prominent. Bone marrow failure is characterized by a generalized marrow cell and microenvironmental dysfunction that does not support and maintain normal hematopoiesis.

Clinical Manifestations.
Although most patients have symptoms of fat malabsorption from birth caused by pancreatic insufficiency, the absence of steatorrhea does not exclude a diagnosis of SDS. Approximately 50% of patients appear to exhibit a modest improvement in pancreatic enzyme secretion with advancing age.

Short stature is a consistent feature of the syndrome; most patients show normal growth velocity, yet remain consistently below the 3rd percentile for height and weight. The occasional adult achieves the 25th percentile for height.

Introduction to DiGeorge Syndrome

DiGeorge syndrome (DGS) now understood to be the chromosome 22q11.2 deletion syndrome was originally described as 3 syndromes found on 2 continents.Dr. DiGeorge was the first to provide clinical examples in humans that demonstrated the thymus was involved in immune function.

Pathophysiology
As the name chromosome 22q11.2 deletion syndrome implies, the syndrome is the result of a 2-3 million base pair (Mb) deletion on the long arm of chromosome 22. This area is prone to microdeletion because of the presence of nonallelic, flanking, low-copy repeat DNA sequences in the region, which lead to unequal crossing over between the two chromosome 22s during meiosis.

Frequency
Estimates of the incidence of chromosome 22q11.2 deletion syndrome range from 1 per 2000-4000 in the general population. It is a frequent cause of cleft palate and congenital heart defects.

Sex
Males and females appear to be equally affected.

Age
This is a congenital condition, but age at diagnosis largely depends on the severity and the types of birth defects. Thus, those with more serious cardiac defects, hypocalcemia, or both observed in classic DGS are diagnosed in the neonatal period. Recurrent infections usually present in patients older than 3-6 months. Some individuals without hypocalcemia who have normal immune function, mild cardiac defects, and minimal facial anomalies may not be diagnosed until late childhood. Late diagnosis into adulthood continues to be reported, especially in those with isolated mild symptoms. Diagnosis in fetuses with a congenital heart anomaly should be offered to the pregnant woman.

Fragile X Syndrome

Fragile X syndrome (FXS), or Martin-Bell syndrome, is a genetic syndrome which results in a spectrum of characteristic physical and intellectual limitations and emotional and behavioral features which range from severe to mild in manifestation.

Frequency
Conservative estimates report that fragile X syndrome affects approximately 1 in 4000 males and 1 in 8000 females.

Pathology
The symptoms of fragile X syndrome are caused by abnormalities in DNA on the X chromosome. Examination of the karyotype reveals a constriction at the end of the long arm of the X chromosome, followed by a thin strand of genetic material. The constriction and thin strand give the appearance of a fragile portion of the X chromosome. Sequencing of the genetic material reveals a repeating base pair triplet that is responsible for the syndrome.

Symptoms and Signs
People with fragile X syndrome have physical, cognitive and behavioral abnormalities. They have large, protuberant ears; a prominent chin and forehead; a high arched palate; and, in postpubertal males, macroorchidism. The joints may be hyperextensible, and heart disease (mitral valve prolapse) may occur. Cognitive abnormalities may include mild to moderate mental retardation. Features of autism may develop, including perseverative speech and behavior, poor eye contact, and social anxiety. Women may experience menopause in their mid-30s.

Approach to Genetic Disorders Presenting with Infantile Hypotonia

Etiology
Hypotonia is a nonspecific sign that may be caused by a wide variety of etiologies.
Dysfunction in any component of the central or peripheral nervous system can cause hypotonia, including diseases of the muscle, neuromuscular junction, nerves, spinal cord, brain stem, cerebellum, basal ganglia, and cerebrum. Central hypotonia with peripheral spastic hypertonia is highly suggestive of central nervous system (CNS) involvement.

Clinical Presentation
Historical features supporting a genetic etiology include family history of neuromuscular disease, parental consanguinity, and a prior affected sibling. However, the absence of these features does not rule out a genetic cause.
Contractures in the newborn indicate prenatal onset but do not suggest a single, specific diagnosis.
Additional features that may indicate an underlying syndrome may not be present at a young age or may be difficult to appreciate in the neonate or infant.

Laboratory Studies
Several tests are recommended in the evaluation of a child with hypotonia and concern for a genetic disorder.

Patau syndrome – Trisomy 13

Patau syndrome, also known as trisomy 13 and trisomy D, is a chromosomal abnormality, a syndrome in which a patient has an additional chromosome 13 due to a nondisjunction of chromosomes during meiosis.

Causes
Trisomy 13 occurs when extra DNA from chromosome 13 appears in some or all of the body’s cells.

• Trisomy 13 — the presence of an extra (third) chromosome 13 in all of the cells.
• Trisomy 13 mosaicism — the presence of an extra chromosome 13 in some of the cells.
• Partial trisomy — the presence of a part of an extra chromosome 13 in the cells.

Incidence

• Patau syndrome is the least common and most severe of the viable autosomal trisomies.
• Trisomy 13 occurs in about 1 out of every 10,000 newborns.
• Median survival is fewer than 3 days, with only one in 20 children surviving longer than 6 months.
• The sex ratio at birth is slightly skewed toward females, presumably because of decreased survival among males.

Clinical Presentation
Newborns with Patau syndrome typically present in the neonatal period with low Apgar scores and may have the following conditions:

• Cleft lip
• Cleft palate
• Polydactyly (postaxial)
• Microcephaly
• Rocker-bottom feet
• Microphthalmia
• Scalp defects (cutis aplasia)
• Omphalocele
• Hernias
• Neural tube defects
• Stillbirth and in utero fetal demise are common pregnancy outcomes
• Cardiac defects occur in 80% of cases
• Holoprosencephaly, in which the brain does not divide completely into halves, is often present and is generally signaled by the presence of midline facial defects. Facial defects include the following:
• Hypotelorism
• Microphthalmia
• Anophthalmia
• Absent or malformed nose or proboscis
• Severe clefting of the lip and/or palate.

Hunter Syndrome - A Rare Genetic Disorder

Introduction:
Hunter syndrome is a rare genetic disorder that occurs due to a deficiency of an enzyme. It is a Lysosomal storage disease and the deficient enzyme is iduronate-2-sulfatase. As a result the long chain of sugar molecules ( mucopolysaccarides) are not broken down by the body and start to accumulate. The accumulated substrates are heparan sulphate and dermatan sulphate. This syndrome has X linked inheritance and so the boys are mostly affected. It is also known as Mucopolysaccharidosis II.

Clinical Features:
The symptoms of Hunter syndrome are usually not apparent at birth. The signs and symptoms usually start to appear around the age of 18 months. The condition varies from patient to patient with some having only minor problems while others showing very sever problems. The signs and symptoms include:

• Growth delay resulting in a short stature
• Delayed development with late walking.
• Change in facial features like thickening of the lips, tongue and nostrils.
• Aggressive behavior.
• Mental function getting worse over time with intellectual disability.
• Claw like hands
• Abnormal bone size and skeletal irregularities.
• Enlarged internal organs like liver and spleen leading to a distended abdomen
• Abdominal hernias.
• Recurrent ear infections, runny nose and cold.
• Deafness getting worse over time.
• Joint stiffness.
• Cardiovascular disorders like progressive thickening of heart valves leading to impaired heart function, high blood pressure and obstruction of blood vessels.
• Respiratory difficulties.
• Carpal tunnel syndrome.