Neurofibromatosis Type 1

Overview

Epidemiology

• Neurofibromatosis type 1 Type 1 Spinal Muscular Atrophy (NF1) is the most common type of neurofibromatosis.
• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: approximately 1 in 2,600–3,000 individuals, regardless of ethnicity and gender Gender Gender Dysphoria
• Inherited in about half of the cases
• Life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids:
  • The mean Mean Mean is the sum of all measurements in a data set divided by the number of measurements in that data set. Measures of Central Tendency and Dispersion age at death is 54.4 years.
  • The median age at death is 59 years.

Etiology

• Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance
• Less commonly, de novo mutations (primarily in paternally derived chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure)

Pathophysiology

• Mutations in the NF1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics located on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 17
• NF1 encodes neurofibromin, a cytoplasmic protein.
  • Predominantly expressed in neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology, Schwann cells, oligodendrocytes, leukocytes Leukocytes White blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). White Myeloid Cells: Histology
  • Multidomain molecule regulating several important intracellular processes:
    • RAS-cyclic AMP pathway
    • Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase Protein kinase A family of enzymes that catalyze the conversion of ATP and a protein to adp and a phosphoprotein. Interferons (MAPK) cascade
    • Adenylyl cyclase
    • Cytoskeletal assembly
  • Also functions as a tumor Tumor Inflammation suppressor
• Involvement of neurofibromin in various pathways explains the wide range of clinical manifestations.

Clinical Presentation

• Café au lait macules (CALMs):
  • Flat, uniformly hyperpigmented macules
  • Appear in the 1st year after birth
  • Increase during early childhood
• Freckling:
  • Appears in the axillary or inguinal regions
  • Apparent by 3–5 years of age
• Lisch nodules:
  • Raised tan-colored hamartomas of the iris
  • More common in adults than in children
• Tumors:
  • Peripheral neurofibromas:
    • Cutaneous
    • Plexiform
    • Nodular
  • Optic pathway gliomas:
    • Low-grade pilocytic astrocytomas
    • Occur in children < 6 years of age
    • Rare in older children and adults
    • Most children have normal vision Vision Ophthalmic Exam.
    • Some gliomas may be symptomatic with progressive visual loss.
  • Other CNS neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors:
    • Low-grade astrocytomas
    • Brainstem gliomas
  • Soft tissue Soft Tissue Soft Tissue Abscess sarcomas:
    • Malignant peripheral nerve sheath tumors
    • Rhabdomyosarcoma
    • GI stromal tumors
    • Glomus tumors
  • Other tumors:
    • Juvenile myelomonocytic leukemia
    • Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
• Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types abnormalities:
  • Long bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types dysplasia and pseudoarthrosis
  • Other bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types lesions:
    • Vertebral defects Vertebral Defects Esophageal Atresia and Tracheoesophageal Fistula
    • Nonossifying fibromas within long bones Long bones Length greater than width. Bones: Structure and Types
    • Sphenoid wing dysplasia
  • Short stature
  • Scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis
  • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
• Neurologic abnormalities:
  • Cognitive deficits and learning disabilities Learning disabilities Conditions characterized by a significant discrepancy between an individual’s perceived level of intellect and their ability to acquire new language and other cognitive skills. These may result from organic or psychological conditions. Relatively common subtypes include dyslexia, dyscalculia, and dysgraphia. DiGeorge Syndrome
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Macrocephaly Macrocephaly Cowden Syndrome
  • Peripheral neuropathy Peripheral Neuropathy Neurofibromatosis Type 2
• Congenital Congenital Chorioretinitis heart disease
• Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
• Vasculopathy
• Other manifestations:
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Irritable bowel syndrome Irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome
  • Pulmonary hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Pulmonary artery Pulmonary artery The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. Lungs: Anatomy stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS)
  • Interstitial lung disease
  • Bullous lung disease
  • Arterial dissection Arterial dissection Arterial dissection is a violation of the structural integrity of the arterial wall that results in blood accumulating between the layers. Dissection of the Carotid and Vertebral Arteries (rare)

Diagnosis

The diagnosis of NF1 is usually made clinically based on the typical clinical presentation and confirmed by genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies.

• Diagnostic criteria: At least 2 features must be present:
  • ≥ 6 CALMs:
    • > 5 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma in diameter in prepubertal individuals
    • > 15 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma in diameter in postpubertal individuals
    • The longest diameter is measured.
    • Ordinary room light is used.
  • ≥ 2 neurofibromas of any type or 1 plexiform neurofibroma
  • Freckling in the axillary or inguinal regions
  • Optic glioma
  • ≥ 2 Lisch nodules
  • A distinctive bony lesion (e.g., sphenoid dysplasia, thickening of the cortex of long bones Long bones Length greater than width. Bones: Structure and Types with or without pseudoarthrosis)
  • A 1st-degree relative (parent, sibling, or offspring) with NF1 defined by the above criteria
• Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies
• Screening Screening Preoperative Care of family members
• Prenatal testing
• Neuroimaging Neuroimaging Non-invasive methods of visualizing the central nervous system, especially the brain, by various imaging modalities. Febrile Infant (MRI or CT), potential findings:
  • Focal bright spots on T2-weighted images T2-Weighted Images Imaging of the Head and Brain (disappear with age)
  • Increased brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification volume
  • Abnormal cerebral vasculature

Management

Tumors

• Cutaneous and subcutaneous neurofibromas
  • Removal by surgery, laser, or electrodesiccation Electrodesiccation Seborrheic Keratosis
  • Indications for removal include:
    • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
    • Bleeding
    • Interference with function
    • Disfigurement
  • Gabapentin Gabapentin A cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of partial seizures; neuralgia; and restless legs syndrome. Second-Generation Anticonvulsant Drugs (for pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema))
• Plexiform neurofibromas:
  • Selumetinib (for tumor Tumor Inflammation regression Regression Corneal Abrasions, Erosion, and Ulcers)
  • Surgical resection (debulking)
  • Imatinib Imatinib A tyrosine kinase inhibitor and antineoplastic agent that inhibits the bcr-abl kinase created by chromosome rearrangements in chronic myeloid leukemia and acute lymphoblastic leukemia, as well as pdg-derived tyrosine kinases that are overexpressed in gastrointestinal stromal tumors. Targeted and Other Nontraditional Antineoplastic Therapy or pegylated interferon (shrinkage)
• Optic pathway gliomas and other low-grade gliomas:
  • Chemotherapy Chemotherapy Osteosarcoma:
    • Carboplatin Carboplatin An organoplatinum compound that possesses antineoplastic activity. Alkylating Agents and Platinum
    • Vincristine Vincristine An antitumor alkaloid isolated from vinca rosea. Microtubule and Topoisomerase Inhibitors
    • Vinblastine Vinblastine Antitumor alkaloid isolated from vinca rosea. Microtubule and Topoisomerase Inhibitors
  • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma (avoided in pediatric individuals)
• High-grade gliomas:
  • Surgical resection
  • Conventional radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma + temozolomide Temozolomide A dacarbazine derivative that is used as an alkylating antineoplastic agent for the treatment of malignant glioma and malignant melanoma. Alkylating Agents and Platinum
• Malignant peripheral nerve sheath tumors:
  • Surgical resection
  • Adjunctive radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy
• Rhabdomyosarcoma:
  • Chemotherapy Chemotherapy Osteosarcoma
  • Surgery, if feasible
  • Radiotherapy
• GI stromal tumors: poorly responsive to imatinib Imatinib A tyrosine kinase inhibitor and antineoplastic agent that inhibits the bcr-abl kinase created by chromosome rearrangements in chronic myeloid leukemia and acute lymphoblastic leukemia, as well as pdg-derived tyrosine kinases that are overexpressed in gastrointestinal stromal tumors. Targeted and Other Nontraditional Antineoplastic Therapy

Neurologic abnormalities

• Cognitive and learning deficits:
  • Learning disabilities Learning disabilities Conditions characterized by a significant discrepancy between an individual’s perceived level of intellect and their ability to acquire new language and other cognitive skills. These may result from organic or psychological conditions. Relatively common subtypes include dyslexia, dyscalculia, and dysgraphia. DiGeorge Syndrome: academic support
  • Speech deficits: speech therapy Speech Therapy Treatment for individuals with speech defects and disorders that involves counseling and use of various exercises and AIDS to help the development of new speech habits. Myotonic Dystrophies
  • Motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology impairment: occupational therapy Occupational Therapy Skilled treatment that helps individuals achieve independence in all facets of their lives. It assists in the development of skills needed for independent living. Fetal Alcohol Spectrum Disorder and PT
• Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures: antiseizure drugs
• Peripheral neuropathy Peripheral Neuropathy Neurofibromatosis Type 2: Treat the underlying cause and alleviate symptoms.

Others

• Psychosocial issues: counseling
• Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension: antihypertensives Antihypertensives The 1st-line medication classes for hypertension include thiazide-like diuretics, angiotensin-converting enzyme inhibitors (ACEis), angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBS). Contraindications, adverse effects, and drug-to-drug interactions are agent specific. Hypertension Drugs
• Genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies for affected individuals and their families

Differential Diagnosis

• Neurofibromatosis type 2 Neurofibromatosis type 2 Neurofibromatosis type 2 is a neurocutaneous disorder that can arise from mutations in the NF2 gene located in chromosome 22 and may be inherited in an autosomal dominant fashion or occur from de novo mutations. The main clinical features are bilateral vestibular schwannomas, intracranial/spinal meningioma, and intramedullary and extramedullary spinal tumors. Neurofibromatosis Type 2: a neurocutaneous disorder that can arise from mutations in the NF2 NF2 Neurofibromatosis type 2 is a neurocutaneous disorder that can arise from mutations in the NF2 gene located in chromosome 22 and may be inherited in an autosomal dominant fashion or occur from de novo mutations. The main clinical features are bilateral vestibular schwannomas, intracranial/spinal meningioma, and intramedullary and extramedullary spinal tumors. Neurofibromatosis Type 2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics. The main clinical features are bilateral vestibular schwannomas Vestibular schwannomas A benign schwannoma of the eighth cranial nerve (vestibulocochlear nerve), mostly arising from the vestibular branch (vestibular nerve) during the fifth or sixth decade of life. Clinical manifestations include hearing loss; headache; vertigo; tinnitus; and facial pain. Bilateral acoustic neuromas are associated with neurofibromatosis 2. Neurofibromatosis Type 2 and intracranial/spinal meningiomas. Diagnosis is made clinically and confirmed based on genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies, MRI, and histopathology. Tumor Tumor Inflammation surveillance Surveillance Developmental Milestones and Normal Growth, follow-up, and screening Screening Preoperative Care of at-risk family members are recommended. Management includes surgical intervention, radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy, and/or monoclonal antibody therapy with bevacizumab Bevacizumab An anti-vegf humanized murine monoclonal antibody. It inhibits vegf receptors and helps to prevent pathologic angiogenesis. Targeted and Other Nontraditional Antineoplastic Therapy.
• Noonan syndrome Noonan syndrome A genetically heterogeneous, multifaceted disorder characterized by short stature, webbed neck, ptosis, skeletal malformations, hypertelorism, hormonal imbalance, cryptorchidism, multiple cardiac abnormalities (most commonly including pulmonary valve stenosis), and some degree of intellectual disability. The phenotype bears similarities to that of turner syndrome that occurs only in females and has its basis in a 45, X karyotype abnormality. Noonan syndrome occurs in both males and females with a normal karyotype (46, XX and 46, xy). Mutations in a several genes (ptpn11, kras, sos1, nf1 and raf1) have been associated the ns phenotype. Mutations in ptpn11 are the most common. Leopard syndrome, a disorder that has clinical features overlapping those of noonan syndrome, is also due to mutations in ptpn11. In addition, there is overlap with the syndrome called neurofibromatosis-noonan syndrome due to mutations in nf1. Hypogonadism: a genetic disorder that occurs following a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in one of several genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure involved in the RAS RAS Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis signaling pathway, especially protein-tyrosine phosphatase, nonreceptor type. Clinical features include short stature, webbed neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess, hypertelorism Hypertelorism Abnormal increase in the interorbital distance due to overdevelopment of the lesser wings of the sphenoid. DiGeorge Syndrome, downward eye slant, low-set ears Low-set ears DiGeorge Syndrome, pulmonic stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS), and CALMs. Management involves the identification Identification Defense Mechanisms and timely monitoring of various clinical presentations.
• Tuberous sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor: an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder that mainly presents with neurocutaneous symptoms. Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the TSC TSC Tuberous sclerosis or tuberous sclerosis complex (TSC) is an autosomal dominant disorder with mainly neurocutaneous symptoms. Mutation in the tsc genes causes excessive tumor-like growths in the brain, eyes, heart, kidney, and lungs. Cutaneous manifestations include hypopigmentation (i.e., ash leaf spots, confetti lesions) or excessive growth (i.e., angiofibroma, shagreen patch). Tuberous Sclerosis gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics causes excessive tumor-like growth in the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification, eyes, heart, kidney, and lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy. Cutaneous manifestations include hypopigmentation Hypopigmentation A condition caused by a deficiency or a loss of melanin pigmentation in the epidermis, also known as hypomelanosis. Hypopigmentation can be localized or generalized, and may result from genetic defects, trauma, inflammation, or infections. Malassezia Fungi (i.e., ash-leaf spots Ash-Leaf Spots Physical Examination of the Newborn) or excessive growth (i.e., angiofibroma Angiofibroma A benign neoplasm of fibrous tissue in which there are numerous small and large, frequently dilated, vascular channels. Tuberous Sclerosis). The diagnosis is made clinically and confirmed by genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. Management entails a multidisciplinary approach that targets the monitoring and treatment of various manifestations of the disorder.
• Constitutional mismatch repair-deficiency syndrome: a rare autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder resulting from the inheritance of deleterious mutations in both copies of 1 of the 4 mismatch-repair genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure. Constitutional mismatch repair-deficiency syndrome results in early-onset (< 18 years of age) hematologic, brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification, or colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy cancers and may present with skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions pigmentations similar to those in NF1. Diagnosis is made clinically. Management is centered around early screening Screening Preoperative Care for tumors and genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies for families of affected individuals.